ID ADT1_HUMAN Reviewed; 298 AA. AC P12235; D3DP59; DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 4. DT 28-JAN-2026, entry version 253. DE RecName: Full=ADP/ATP translocase 1 {ECO:0000305}; DE AltName: Full=ADP,ATP carrier protein 1 {ECO:0000250|UniProtKB:P48962}; DE AltName: Full=ADP,ATP carrier protein, heart/skeletal muscle isoform T1 {ECO:0000303|PubMed:2541251}; DE AltName: Full=Adenine nucleotide translocator 1 {ECO:0000303|PubMed:2823266}; DE Short=ANT 1 {ECO:0000303|PubMed:2823266}; DE AltName: Full=Solute carrier family 25 member 4 {ECO:0000305}; GN Name=SLC25A4 {ECO:0000303|PubMed:25732997, ECO:0000312|HGNC:HGNC:10990}; GN Synonyms=AAC1 {ECO:0000250|UniProtKB:P48962}, GN ANT1 {ECO:0000303|PubMed:2823266}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=2823266; DOI=10.1073/pnas.84.21.7580; RA Neckelmann N., Li K., Wade R.P., Shuster R., Wallace D.C.; RT "cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a RT leader peptide, divergence from a fibroblast translocator cDNA, and RT coevolution with mitochondrial DNA genes."; RL Proc. Natl. Acad. Sci. U.S.A. 84:7580-7584(1987). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=2541251; DOI=10.1016/0022-2836(89)90477-4; RA Cozens A.L., Runswick M.J., Walker J.E.; RT "DNA sequences of two expressed nuclear genes for human mitochondrial RT ADP/ATP translocase."; RL J. Mol. Biol. 206:261-280(1989). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2547778; DOI=10.1016/s0021-9258(18)71632-3; RA Li K., Warner C.K., Hodge J.A., Minoshima S., Kudoh J., Fukuyama R., RA Maekawa M., Shimizu Y., Shimizu N., Wallace D.C.; RT "A human muscle adenine nucleotide translocator gene has four exons, is RT located on chromosome 4, and is differentially expressed."; RL J. Biol. Chem. 264:13998-14004(1989). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=20843780; DOI=10.1093/nar/gkq750; RA Wang W., Shen P., Thiyagarajan S., Lin S., Palm C., Horvath R., RA Klopstock T., Cutler D., Pique L., Schrijver I., Davis R.W., Mindrinos M., RA Speed T.P., Scharfe C.; RT "Identification of rare DNA variants in mitochondrial disorders with RT improved array-based sequencing."; RL Nucleic Acids Res. 39:44-58(2011). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Eye, Mammary gland, and PNS; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-37. RC TISSUE=Liver; RX PubMed=2829183; DOI=10.1073/pnas.85.2.377; RA Houldsworth J., Attardi G.; RT "Two distinct genes for ADP/ATP translocase are expressed at the mRNA level RT in adult human liver."; RL Proc. Natl. Acad. Sci. U.S.A. 85:377-381(1988). RN [8] RP PROTEIN SEQUENCE OF 2-31; 34-43; 64-92; 141-147; 189-199 AND 273-296, RP CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT GLY-2, AND IDENTIFICATION RP BY MASS SPECTROMETRY. RC TISSUE=B-cell lymphoma; RA Bienvenut W.V.; RL Submitted (OCT-2004) to UniProtKB. RN [9] RP INTERACTION WITH HIV-1 VPR (MICROBIAL INFECTION). RX PubMed=16120388; DOI=10.1016/j.mito.2004.06.012; RA Deniaud A., Brenner C., Kroemer G.; RT "Mitochondrial membrane permeabilization by HIV-1 Vpr."; RL Mitochondrion 4:223-233(2004). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION, RP AND CHARACTERIZATION OF VARIANTS PEOA2 PRO-114 AND MET-289. RX PubMed=21586654; DOI=10.1093/hmg/ddr200; RA Kawamata H., Tiranti V., Magrane J., Chinopoulos C., Manfredi G.; RT "adPEO mutations in ANT1 impair ADP-ATP translocation in muscle RT mitochondria."; RL Hum. Mol. Genet. 20:2964-2974(2011). RN [13] RP INVOLVEMENT IN MTDPS12B. RX PubMed=22187496; DOI=10.1136/jmedgenet-2011-100504; RA Echaniz-Laguna A., Chassagne M., Ceresuela J., Rouvet I., Padet S., RA Acquaviva C., Nataf S., Vinzio S., Bozon D., Mousson de Camaret B.; RT "Complete loss of expression of the ANT1 gene causing cardiomyopathy and RT myopathy."; RL J. Med. Genet. 49:146-150(2012). RN [14] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=23173940; DOI=10.3109/09687688.2012.745175; RA Mifsud J., Ravaud S., Krammer E.M., Chipot C., Kunji E.R., RA Pebay-Peyroula E., Dehez F.; RT "The substrate specificity of the human ADP/ATP carrier AAC1."; RL Mol. Membr. Biol. 30:160-168(2013). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [16] RP FUNCTION, INVOLVEMENT IN MTDPS12A, VARIANTS MTDPS12A HIS-80 AND GLY-235, RP CHARACTERIZATION OF VARIANTS MTDPS12A HIS-80 AND GLY-235, CHARACTERIZATION RP OF VARIANTS PEOA2 ASP-90; PRO-98; GLY-104 AND PRO-114, AND CHARACTERIZATION RP OF VARIANTS MTDPS12B ASP-123 AND PRO-236. RX PubMed=27693233; DOI=10.1016/j.ajhg.2016.08.014; RA Thompson K., Majd H., Dallabona C., Reinson K., King M.S., Alston C.L., RA He L., Lodi T., Jones S.A., Fattal-Valevski A., Fraenkel N.D., Saada A., RA Haham A., Isohanni P., Vara R., Barbosa I.A., Simpson M.A., Deshpande C., RA Puusepp S., Bonnen P.E., Rodenburg R.J., Suomalainen A., Ounap K., RA Elpeleg O., Ferrero I., McFarland R., Kunji E.R., Taylor R.W.; RT "Recurrent de novo dominant mutations in SLC25A4 cause severe early-onset RT mitochondrial disease and loss of mitochondrial DNA copy number."; RL Am. J. Hum. Genet. 99:860-876(2016). RN [17] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RX PubMed=27641616; DOI=10.1038/srep33516; RA Marginedas-Freixa I., Hattab C., Bouyer G., Halle F., Chene A., RA Lefevre S.D., Cambot M., Cueff A., Schmitt M., Gamain B., Lacapere J.J., RA Egee S., Bihel F., Le Van Kim C., Ostuni M.A.; RT "TSPO ligands stimulate ZnPPIX transport and ROS accumulation leading to RT the inhibition of P. falciparum growth in human blood."; RL Sci. Rep. 6:33516-33516(2016). RN [18] RP FUNCTION, AND INTERACTION WITH ARHGAP11B. RX PubMed=31883789; DOI=10.1016/j.neuron.2019.11.027; RA Namba T., Doczi J., Pinson A., Xing L., Kalebic N., Wilsch-Braeuninger M., RA Long K.R., Vaid S., Lauer J., Bogdanova A., Borgonovo B., Shevchenko A., RA Keller P., Drechsel D., Kurzchalia T., Wimberger P., Chinopoulos C., RA Huttner W.B.; RT "Human-specific ARHGAP11B acts in mitochondria to expand neocortical RT progenitors by glutaminolysis."; RL Neuron 105:867-881(2020). RN [19] RP FUNCTION. RX PubMed=37278158; DOI=10.15252/embr.202357127; RA Cimadamore-Werthein C., Jaiquel Baron S., King M.S., Springett R., RA Kunji E.R.; RT "Human mitochondrial ADP/ATP carrier SLC25A4 operates with a ping-pong RT kinetic mechanism."; RL EMBO Rep. 24:e57127-e57127(2023). RN [20] RP VARIANTS PEOA2 PRO-114 AND MET-289. RX PubMed=10926541; DOI=10.1126/science.289.5480.782; RA Kaukonen J., Juselius J.K., Tiranti V., Kyttala A., Zeviani M., Comi G.P., RA Keranen J., Peltonen L., Suomalainen A.; RT "Role of adenine nucleotide translocator 1 in mtDNA maintenance."; RL Science 289:782-785(2000). RN [21] RP VARIANT PEOA2 PRO-98. RX PubMed=11756613; DOI=10.1212/wnl.57.12.2295; RA Napoli L., Bordoni A., Zeviani M., Hadjigeorgiou G.M., Sciacco M., RA Tiranti V., Terentiou A., Moggio M., Papadimitriou A., Scarlato G., RA Comi G.P.; RT "A novel missense adenine nucleotide translocator-1 gene mutation in a RT Greek adPEO family."; RL Neurology 57:2295-2298(2001). RN [22] RP VARIANT PEOA2 GLY-104. RX PubMed=12112115; DOI=10.1002/ana.10172; RA Komaki H., Fukazawa T., Houzen H., Yoshida K., Nonaka I., Goto Y.; RT "A novel D104G mutation in the adenine nucleotide translocator 1 gene in RT autosomal dominant progressive external ophthalmoplegia patients with RT mitochondrial DNA with multiple deletions."; RL Ann. Neurol. 51:645-648(2002). RN [23] RP VARIANT PEOA2 MET-289. RX PubMed=12707443; DOI=10.1212/01.wnl.0000056088.09408.3c; RA Agostino A., Valletta L., Chinnery P.F., Ferrari G., Carrara F., RA Taylor R.W., Schaefer A.M., Turnbull D.M., Tiranti V., Zeviani M.; RT "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external RT ophthalmoplegia (PEO)."; RL Neurology 60:1354-1356(2003). RN [24] RP VARIANT MTDPS12B ASP-123. RX PubMed=16155110; DOI=10.1093/hmg/ddi341; RA Palmieri L., Alberio S., Pisano I., Lodi T., Meznaric-Petrusa M., Zidar J., RA Santoro A., Scarcia P., Fontanesi F., Lamantea E., Ferrero I., Zeviani M.; RT "Complete loss-of-function of the heart/muscle-specific adenine nucleotide RT translocator is associated with mitochondrial myopathy and RT cardiomyopathy."; RL Hum. Mol. Genet. 14:3079-3088(2005). RN [25] RP VARIANT PEOA2 ASP-90. RX PubMed=15792871; DOI=10.1016/j.nmd.2004.12.004; RA Deschauer M., Hudson G., Mueller T., Taylor R.W., Chinnery P.F., Zierz S.; RT "A novel ANT1 gene mutation with probable germline mosaicism in autosomal RT dominant progressive external ophthalmoplegia."; RL Neuromuscul. Disord. 15:311-315(2005). RN [26] RP VARIANTS PEOA2 PRO-98 AND PRO-114. RX PubMed=18575922; DOI=10.1007/s00415-008-0926-3; RA Virgilio R., Ronchi D., Hadjigeorgiou G.M., Bordoni A., Saladino F., RA Moggio M., Adobbati L., Kafetsouli D., Tsironi E., Previtali S., RA Papadimitriou A., Bresolin N., Comi G.P.; RT "Novel Twinkle (PEO1) gene mutations in Mendelian progressive external RT ophthalmoplegia."; RL J. Neurol. 255:1384-1391(2008). RN [27] RP VARIANT MTDPS12B PRO-236. RX PubMed=25732997; DOI=10.1007/8904_2015_409; RA Koerver-Keularts I.M., de Visser M., Bakker H.D., Wanders R.J., RA Vansenne F., Scholte H.R., Dorland L., Nicolaes G.A., Spaapen L.M., RA Smeets H.J., Hendrickx A.T., van den Bosch B.J.; RT "Two novel mutations in the SLC25A4 gene in a patient with mitochondrial RT myopathy."; RL JIMD Rep. 22:39-45(2015). RN [28] RP VARIANT GLN-33, CHARACTERIZATION OF VARIANT GLN-33, AND FUNCTION. RX PubMed=30046662; DOI=10.1212/nxg.0000000000000256; RA King M.S., Thompson K., Hopton S., He L., Kunji E.R.S., Taylor R.W., RA Ortiz-Gonzalez X.R.; RT "Expanding the phenotype of de novo SLC25A4-linked mitochondrial disease to RT include mild myopathy."; RL Neurol. Genet. 4:e256-e256(2018). CC -!- FUNCTION: ADP:ATP antiporter that mediates import of ADP into the CC mitochondrial matrix for ATP synthesis, and export of ATP out to fuel CC the cell (PubMed:21586654, PubMed:27693233, PubMed:23173940, CC PubMed:30046662). Cycles between the cytoplasmic-open state (c-state) CC and the matrix-open state (m-state): operates by the alternating access CC mechanism with a single substrate-binding site intermittently exposed CC to either the cytosolic (c-state) or matrix (m-state) side of the inner CC mitochondrial membrane (By similarity). Substrate exchange across the CC membrane occurs consecutively with one substrate being transported CC first, then dissociating from the substrate binding site before the CC second substrate binds for transport in the opposite direction CC (PubMed:37278158). In addition to its ADP:ATP antiporter activity, also CC involved in mitochondrial uncoupling and mitochondrial permeability CC transition pore (mPTP) activity (PubMed:31883789). Plays a role in CC mitochondrial uncoupling by acting as a proton transporter: proton CC transport uncouples the proton flows via the electron transport chain CC and ATP synthase to reduce the efficiency of ATP production and cause CC mitochondrial thermogenesis (By similarity). Proton transporter CC activity is inhibited by ADP:ATP antiporter activity, suggesting that CC SLC25A4/ANT1 acts as a master regulator of mitochondrial energy output CC by maintaining a delicate balance between ATP production (ADP:ATP CC antiporter activity) and thermogenesis (proton transporter activity) CC (By similarity). Proton transporter activity requires free fatty acids CC as cofactor, but does not transport it (By similarity). Also plays a CC key role in mPTP opening, a non-specific pore that enables free passage CC of the mitochondrial membranes to solutes of up to 1.5 kDa, and which CC contributes to cell death (PubMed:31883789). It is however unclear if CC SLC25A4/ANT1 constitutes a pore-forming component of mPTP or regulates CC it (By similarity). Acts as a regulator of mitophagy independently of CC ADP:ATP antiporter activity: promotes mitophagy via interaction with CC TIMM44, leading to inhibit the presequence translocase TIMM23, thereby CC promoting stabilization of PINK1 (By similarity). CC {ECO:0000250|UniProtKB:G2QNH0, ECO:0000250|UniProtKB:P48962, CC ECO:0000269|PubMed:21586654, ECO:0000269|PubMed:23173940, CC ECO:0000269|PubMed:27693233, ECO:0000269|PubMed:31883789, CC ECO:0000269|PubMed:37278158}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ADP(in) + ATP(out) = ADP(out) + ATP(in); Xref=Rhea:RHEA:34999, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:456216; CC Evidence={ECO:0000269|PubMed:21586654, ECO:0000269|PubMed:23173940}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+)(in) = H(+)(out); Xref=Rhea:RHEA:34979, ChEBI:CHEBI:15378; CC Evidence={ECO:0000250|UniProtKB:P48962}; CC -!- ACTIVITY REGULATION: The matrix-open state (m-state) is inhibited by CC the membrane-permeable bongkrekic acid (BKA) PubMed:23173940. The CC cytoplasmic-open state (c-state) is inhibited by the membrane- CC impermeable toxic inhibitor carboxyatractyloside (CATR) CC (PubMed:21586654, PubMed:23173940). Proton transporter activity is CC inhibited by ADP:ATP antiporter activity (By similarity). CC {ECO:0000250|UniProtKB:G2QNH0, ECO:0000250|UniProtKB:P48962, CC ECO:0000269|PubMed:21586654}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=23.7 uM for ATP {ECO:0000269|PubMed:23173940}; CC Vmax=14.6 nmol/min/mg enzyme for ATP uptake CC {ECO:0000269|PubMed:23173940}; CC -!- SUBUNIT: Monomer (By similarity). Found in a complex with ARL2, ARL2BP CC and SLC25A4/ANT1 (By similarity). Interacts with ARL2BP (By CC similarity). Interacts with ARHGAP11B, thereby inhibiting the CC mitochondrial permeability transition pore (mPTP) (PubMed:31883789). CC Interacts with TIMM44; leading to inhibit the presequence translocase CC TIMM23, thereby promoting stabilization of PINK1 (By similarity). CC {ECO:0000250|UniProtKB:G2QNH0, ECO:0000250|UniProtKB:P02722, CC ECO:0000250|UniProtKB:P48962, ECO:0000269|PubMed:31883789}. CC -!- SUBUNIT: (Microbial infection) Interacts with HIV-1 Vpr. CC {ECO:0000269|PubMed:16120388}. CC -!- INTERACTION: CC P12235; Q5S007: LRRK2; NbExp=2; IntAct=EBI-359074, EBI-5323863; CC P12235; P22736-1: NR4A1; NbExp=2; IntAct=EBI-359074, EBI-16085263; CC P12235; P12236: SLC25A6; NbExp=2; IntAct=EBI-359074, EBI-356254; CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane CC {ECO:0000269|PubMed:21586654}; Multi-pass membrane protein CC {ECO:0000255}. Membrane {ECO:0000269|PubMed:27641616}; Multi-pass CC membrane protein {ECO:0000255}. Note=The complex formed with ARL2BP, CC ARL2 and SLC25A4/ANT1 is expressed in mitochondria (By similarity). May CC localize to non-mitochondrial membranes (PubMed:27641616). CC {ECO:0000250|UniProtKB:P48962, ECO:0000269|PubMed:27641616}. CC -!- TISSUE SPECIFICITY: Expressed in erythrocytes (at protein level). CC {ECO:0000269|PubMed:27641616}. CC -!- DOMAIN: The transmembrane helices are not perpendicular to the plane of CC the membrane, but cross the membrane at an angle. Odd-numbered CC transmembrane helices exhibit a sharp kink, due to the presence of a CC conserved proline residue. {ECO:0000250|UniProtKB:P02722}. CC -!- PTM: Under cell death induction, transglutaminated by TGM2. CC Transglutamination leads to formation of covalent cross-links between a CC glutamine and the epsilon-amino group of a lysine residue, forming CC polymers. {ECO:0000250|UniProtKB:P48962}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 2 (PEOA2) [MIM:609283]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:10926541, CC ECO:0000269|PubMed:11756613, ECO:0000269|PubMed:12112115, CC ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:15792871, CC ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:21586654, CC ECO:0000269|PubMed:27693233}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 12B, cardiomyopathic type CC (MTDPS12B) [MIM:615418]: An autosomal recessive mitochondrial disorder CC characterized by childhood onset of slowly progressive hypertrophic CC cardiomyopathy and generalized skeletal myopathy resulting in exercise CC intolerance and, in some patients, muscle weakness and atrophy. CC Skeletal muscle biopsy shows ragged red fibers, mtDNA depletion, and CC accumulation of abnormal mitochondria. {ECO:0000269|PubMed:16155110, CC ECO:0000269|PubMed:22187496, ECO:0000269|PubMed:25732997, CC ECO:0000269|PubMed:27693233}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 12A, cardiomyopathic type CC (MTDPS12A) [MIM:617184]: An autosomal dominant mitochondrial disorder CC characterized by severe hypotonia due to mitochondrial dysfunction CC apparent at birth. Affected infants have respiratory insufficiency CC requiring mechanical ventilation and have poor or no motor development. CC Many die in infancy, and those that survive have profound hypotonia CC with significant muscle weakness and inability to walk independently. CC Some patients develop hypertrophic cardiomyopathy. Muscle samples show CC mtDNA depletion and severe combined mitochondrial respiratory chain CC deficiencies. {ECO:0000269|PubMed:27693233}. Note=The disease is caused CC by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the mitochondrial carrier (TC 2.A.29) family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; J02966; AAA61223.1; -; mRNA. DR EMBL; J04982; AAA51736.1; -; Genomic_DNA. DR EMBL; HQ206346; ADP92294.1; -; Genomic_DNA. DR EMBL; HQ206347; ADP92295.1; -; Genomic_DNA. DR EMBL; HQ206348; ADP92296.1; -; Genomic_DNA. DR EMBL; HQ206349; ADP92297.1; -; Genomic_DNA. DR EMBL; HQ206350; ADP92298.1; -; Genomic_DNA. DR EMBL; HQ206351; ADP92299.1; -; Genomic_DNA. DR EMBL; HQ206352; ADP92300.1; -; Genomic_DNA. DR EMBL; HQ206353; ADP92301.1; -; Genomic_DNA. DR EMBL; HQ206354; ADP92302.1; -; Genomic_DNA. DR EMBL; HQ206355; ADP92303.1; -; Genomic_DNA. DR EMBL; HQ206356; ADP92304.1; -; Genomic_DNA. DR EMBL; HQ206357; ADP92305.1; -; Genomic_DNA. DR EMBL; HQ206358; ADP92306.1; -; Genomic_DNA. DR EMBL; HQ206359; ADP92307.1; -; Genomic_DNA. DR EMBL; HQ206360; ADP92308.1; -; Genomic_DNA. DR EMBL; HQ206361; ADP92309.1; -; Genomic_DNA. DR EMBL; HQ206362; ADP92310.1; -; Genomic_DNA. DR EMBL; HQ206363; ADP92311.1; -; Genomic_DNA. DR EMBL; HQ206364; ADP92312.1; -; Genomic_DNA. DR EMBL; HQ206365; ADP92313.1; -; Genomic_DNA. DR EMBL; HQ206366; ADP92314.1; -; Genomic_DNA. DR EMBL; HQ206367; ADP92315.1; -; Genomic_DNA. DR EMBL; HQ206368; ADP92316.1; -; Genomic_DNA. DR EMBL; HQ206369; ADP92317.1; -; Genomic_DNA. DR EMBL; HQ206370; ADP92318.1; -; Genomic_DNA. DR EMBL; HQ206371; ADP92319.1; -; Genomic_DNA. DR EMBL; HQ206372; ADP92320.1; -; Genomic_DNA. DR EMBL; HQ206373; ADP92321.1; -; Genomic_DNA. DR EMBL; HQ206374; ADP92322.1; -; Genomic_DNA. DR EMBL; HQ206375; ADP92323.1; -; Genomic_DNA. DR EMBL; HQ206376; ADP92324.1; -; Genomic_DNA. DR EMBL; HQ206377; ADP92325.1; -; Genomic_DNA. DR EMBL; HQ206378; ADP92326.1; -; Genomic_DNA. DR EMBL; HQ206379; ADP92327.1; -; Genomic_DNA. DR EMBL; HQ206380; ADP92328.1; -; Genomic_DNA. DR EMBL; HQ206381; ADP92329.1; -; Genomic_DNA. DR EMBL; HQ206382; ADP92330.1; -; Genomic_DNA. DR EMBL; HQ206383; ADP92331.1; -; Genomic_DNA. DR EMBL; HQ206384; ADP92332.1; -; Genomic_DNA. DR EMBL; HQ206385; ADP92333.1; -; Genomic_DNA. DR EMBL; CH471056; EAX04655.1; -; Genomic_DNA. DR EMBL; CH471056; EAX04656.1; -; Genomic_DNA. DR EMBL; BC008664; AAH08664.1; -; mRNA. DR EMBL; BC061589; AAH61589.1; -; mRNA. DR EMBL; BC063643; AAH63643.1; -; mRNA. DR EMBL; J03593; AAA36751.1; -; mRNA. DR CCDS; CCDS34114.1; -. DR PIR; A44778; A44778. DR RefSeq; NP_001142.2; NM_001151.4. DR AlphaFoldDB; P12235; -. DR SMR; P12235; -. DR BioGRID; 106788; 352. DR DIP; DIP-33116N; -. DR FunCoup; P12235; 1978. DR IntAct; P12235; 125. DR MINT; P12235; -. DR STRING; 9606.ENSP00000281456; -. DR DrugBank; DB01736; [3-(Dodecanoylamino)Propyl](Hydroxy)Dimethylammonium. DR DrugBank; DB00171; ATP. DR DrugBank; DB02426; Carboxyatractyloside. DR DrugBank; DB00720; Clodronic acid. DR DrugBank; DB04178; Di-Stearoyl-3-Sn-Phosphatidylcholine. DR DrugBank; DB01077; Etidronic acid. DR DrugBank; DB03429; Tetrastearoyl cardiolipin. DR DrugCentral; P12235; -. DR MoonProt; P12235; -. DR TCDB; 2.A.29.1.2; the mitochondrial carrier (mc) family. DR GlyGen; P12235; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P12235; -. DR MetOSite; P12235; -. DR PhosphoSitePlus; P12235; -. DR SwissPalm; P12235; -. DR BioMuta; SLC25A4; -. DR DMDM; 113455; -. DR jPOST; P12235; -. DR MassIVE; P12235; -. DR PaxDb; 9606-ENSP00000281456; -. DR PeptideAtlas; P12235; -. DR ProteomicsDB; 52836; -. DR Pumba; P12235; -. DR TopDownProteomics; P12235; -. DR Antibodypedia; 28911; 156 antibodies from 24 providers. DR DNASU; 291; -. DR Ensembl; ENST00000281456.11; ENSP00000281456.5; ENSG00000151729.12. DR GeneID; 291; -. DR KEGG; hsa:291; -. DR MANE-Select; ENST00000281456.11; ENSP00000281456.5; NM_001151.4; NP_001142.2. DR UCSC; uc003ixd.4; human. DR AGR; HGNC:10990; -. DR ClinPGx; PA35866; -. DR CTD; 291; -. DR DisGeNET; 291; -. DR GeneCards; SLC25A4; -. DR HGNC; HGNC:10990; SLC25A4. DR HPA; ENSG00000151729; Group enriched (heart muscle, skeletal muscle, tongue). DR MalaCards; SLC25A4; -. DR MIM; 103220; gene. DR MIM; 609283; phenotype. DR MIM; 615418; phenotype. DR MIM; 617184; phenotype. DR OpenTargets; ENSG00000151729; -. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 1369; Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome. DR VEuPathDB; HostDB:ENSG00000151729; -. DR eggNOG; KOG0749; Eukaryota. DR GeneTree; ENSGT00940000154622; -. DR InParanoid; P12235; -. DR OMA; HPAMYQR; -. DR OrthoDB; 270584at2759; -. DR PAN-GO; P12235; 4 GO annotations based on evolutionary models. DR PhylomeDB; P12235; -. DR PathwayCommons; P12235; -. DR Reactome; R-HSA-1268020; Mitochondrial protein import. DR Reactome; R-HSA-166187; Mitochondrial Uncoupling. DR Reactome; R-HSA-180897; Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization. DR Reactome; R-HSA-83936; Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane. DR SignaLink; P12235; -. DR SIGNOR; P12235; -. DR Agora; ENSG00000151729; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 291; 14 hits in 1168 CRISPR screens. DR CD-CODE; 91857CE7; Nucleolus. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; SLC25A4; human. DR GeneWiki; SLC25A4; -. DR GenomeRNAi; 291; -. DR Pharos; P12235; Tbio. DR PRO; PR:P12235; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P12235; protein. DR Bgee; ENSG00000151729; Expressed in left ventricle myocardium and 209 other cell types or tissues. DR ExpressionAtlas; P12235; baseline and differential. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:UniProtKB. DR GO; GO:0031966; C:mitochondrial membrane; ISS:UniProtKB. DR GO; GO:0005757; C:mitochondrial permeability transition pore complex; ISS:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; TAS:ProtInc. DR GO; GO:0015207; F:adenine transmembrane transporter activity; TAS:ProtInc. DR GO; GO:0005471; F:ATP:ADP antiporter activity; IDA:UniProtKB. DR GO; GO:0017077; F:oxidative phosphorylation uncoupler activity; ISS:UniProtKB. DR GO; GO:0015078; F:proton transmembrane transporter activity; TAS:Reactome. DR GO; GO:1990845; P:adaptive thermogenesis; ISS:UniProtKB. DR GO; GO:0015866; P:ADP transport; IMP:UniProtKB. DR GO; GO:0008637; P:apoptotic mitochondrial changes; IEA:Ensembl. DR GO; GO:0006091; P:generation of precursor metabolites and energy; TAS:ProtInc. DR GO; GO:0140021; P:mitochondrial ADP transmembrane transport; IDA:UniProtKB. DR GO; GO:1990544; P:mitochondrial ATP transmembrane transport; IDA:UniProtKB. DR GO; GO:1901029; P:negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; IBA:GO_Central. DR GO; GO:0060546; P:negative regulation of necroptotic process; IMP:BHF-UCL. DR GO; GO:1901526; P:positive regulation of mitophagy; ISS:UniProtKB. DR GO; GO:0046902; P:regulation of mitochondrial membrane permeability; ISS:UniProtKB. DR FunFam; 1.50.40.10:FF:000002; Putative ADP/ATP translocase 2-like; 1. DR Gene3D; 1.50.40.10; Mitochondrial carrier domain; 1. DR InterPro; IPR002113; ADT_euk_type. DR InterPro; IPR002067; MCP. DR InterPro; IPR023395; MCP_dom_sf. DR InterPro; IPR018108; MCP_transmembrane. DR PANTHER; PTHR45635; ADP,ATP CARRIER PROTEIN 1-RELATED-RELATED; 1. DR PANTHER; PTHR45635:SF32; ADP_ATP TRANSLOCASE 1; 1. DR Pfam; PF00153; Mito_carr; 3. DR PRINTS; PR00927; ADPTRNSLCASE. DR PRINTS; PR00926; MITOCARRIER. DR SUPFAM; SSF103506; Mitochondrial carrier; 1. DR PROSITE; PS50920; SOLCAR; 3. PE 1: Evidence at protein level; KW Acetylation; Antiport; ATP-binding; Cardiomyopathy; KW Direct protein sequencing; Disease variant; Host-virus interaction; KW Membrane; Methylation; Mitochondrion; Mitochondrion inner membrane; KW Nucleotide-binding; Phosphoprotein; Primary mitochondrial disease; KW Progressive external ophthalmoplegia; Proteomics identification; KW Reference proteome; Repeat; S-nitrosylation; Transmembrane; KW Transmembrane helix; Transport. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|Ref.8" FT CHAIN 2..298 FT /note="ADP/ATP translocase 1" FT /id="PRO_0000090574" FT TOPO_DOM 2..7 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305" FT TRANSMEM 8..37 FT /note="Helical; Name=1" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 38..74 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000305" FT TRANSMEM 75..99 FT /note="Helical; Name=2" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 100..109 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305" FT TRANSMEM 110..130 FT /note="Helical; Name=3" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 131..178 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000305" FT TRANSMEM 179..199 FT /note="Helical; Name=4" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 200..210 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305" FT TRANSMEM 211..231 FT /note="Helical; Name=5" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 232..273 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000305" FT TRANSMEM 274..291 FT /note="Helical; Name=6" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 292..298 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305" FT REPEAT 6..98 FT /note="Solcar 1" FT REPEAT 111..201 FT /note="Solcar 2" FT REPEAT 212..297 FT /note="Solcar 3" FT REGION 235..240 FT /note="Important for transport activity" FT /evidence="ECO:0000269|PubMed:27693233" FT MOTIF 235..240 FT /note="Nucleotide carrier signature motif" FT /evidence="ECO:0000250|UniProtKB:P02722" FT BINDING 80 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:P02722" FT BINDING 92 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:P02722" FT BINDING 235 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:P02722" FT MOD_RES 2 FT /note="N-acetylglycine" FT /evidence="ECO:0000269|Ref.8" FT MOD_RES 7 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q05962" FT MOD_RES 52 FT /note="N6,N6,N6-trimethyllysine" FT /evidence="ECO:0000250|UniProtKB:Q05962" FT MOD_RES 147 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P48962" FT MOD_RES 160 FT /note="S-nitrosocysteine" FT /evidence="ECO:0000250|UniProtKB:Q05962" FT MOD_RES 245 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P48962" FT MOD_RES 272 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P48962" FT VARIANT 33 FT /note="K -> Q (found in a patient with mild childhood-onset FT myopathy without evidence of other clinical features such FT as cardiomyopathy, encephalopathy or ophthalmoplegia; FT likely pathogenic; abolishes ADP transport)" FT /evidence="ECO:0000269|PubMed:30046662" FT /id="VAR_090742" FT VARIANT 80 FT /note="R -> H (in MTDPS12A; decreased function in ADP FT transport; dbSNP:rs886041081)" FT /evidence="ECO:0000269|PubMed:27693233" FT /id="VAR_078071" FT VARIANT 90 FT /note="A -> D (in PEOA2; decreased function in ADP FT transport)" FT /evidence="ECO:0000269|PubMed:15792871, FT ECO:0000269|PubMed:27693233" FT /id="VAR_038814" FT VARIANT 98 FT /note="L -> P (in PEOA2; decreased function in ADP FT transport; dbSNP:rs104893876)" FT /evidence="ECO:0000269|PubMed:11756613, FT ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:27693233" FT /id="VAR_022459" FT VARIANT 104 FT /note="D -> G (in PEOA2; decreased function in ADP FT transport; dbSNP:rs28999114)" FT /evidence="ECO:0000269|PubMed:12112115, FT ECO:0000269|PubMed:27693233" FT /id="VAR_022460" FT VARIANT 114 FT /note="A -> P (in PEOA2; decreased function in ADP FT transport; inverted direction of ADP:ATP transport, with FT ATP entering the mitochondrial matrix; dbSNP:rs104893873)" FT /evidence="ECO:0000269|PubMed:10926541, FT ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:21586654, FT ECO:0000269|PubMed:27693233" FT /id="VAR_012111" FT VARIANT 123 FT /note="A -> D (in MTDPS12B; loss of function in ADP FT transport; dbSNP:rs121912683)" FT /evidence="ECO:0000269|PubMed:16155110, FT ECO:0000269|PubMed:27693233" FT /id="VAR_038815" FT VARIANT 235 FT /note="R -> G (in MTDPS12A; severely decreased function in FT ADP transport; dbSNP:rs886041082)" FT /evidence="ECO:0000269|PubMed:27693233" FT /id="VAR_078072" FT VARIANT 236 FT /note="R -> P (in MTDPS12B; loss of function in ADP FT transport; dbSNP:rs770816416)" FT /evidence="ECO:0000269|PubMed:25732997, FT ECO:0000269|PubMed:27693233" FT /id="VAR_078073" FT VARIANT 289 FT /note="V -> M (in PEOA2; inverted direction of ADP:ATP FT transport, with ATP entering the mitochondrial matrix; FT dbSNP:rs104893874)" FT /evidence="ECO:0000269|PubMed:10926541, FT ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:21586654" FT /id="VAR_012112" FT CONFLICT 16 FT /note="G -> A (in Ref. 1; AAA61223)" FT /evidence="ECO:0000305" FT CONFLICT 147..149 FT /note="KGA -> RR (in Ref. 1; AAA61223)" FT /evidence="ECO:0000305" FT CONFLICT 227 FT /note="V -> L (in Ref. 1; AAA61223)" FT /evidence="ECO:0000305" SQ SEQUENCE 298 AA; 33064 MW; 59F0DFAEC4E7CFBB CRC64; MGDHAWSFLK DFLAGGVAAA VSKTAVAPIE RVKLLLQVQH ASKQISAEKQ YKGIIDCVVR IPKEQGFLSF WRGNLANVIR YFPTQALNFA FKDKYKQLFL GGVDRHKQFW RYFAGNLASG GAAGATSLCF VYPLDFARTR LAADVGKGAA QREFHGLGDC IIKIFKSDGL RGLYQGFNVS VQGIIIYRAA YFGVYDTAKG MLPDPKNVHI FVSWMIAQSV TAVAGLVSYP FDTVRRRMMM QSGRKGADIM YTGTVDCWRK IAKDEGAKAF FKGAWSNVLR GMGGAFVLVL YDEIKKYV // ID DCTN1_HUMAN Reviewed; 1278 AA. AC Q14203; A8MY36; B4DM45; E9PFS5; E9PGE1; G5E9H4; O95296; Q6IQ37; Q9BRM9; AC Q9UIU1; Q9UIU2; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 18-OCT-2001, sequence version 3. DT 28-JAN-2026, entry version 231. DE RecName: Full=Dynactin subunit 1; DE AltName: Full=150 kDa dynein-associated polypeptide; DE AltName: Full=DAP-150; DE Short=DP-150; DE AltName: Full=p135; DE AltName: Full=p150-glued; GN Name=DCTN1 {ECO:0000312|HGNC:HGNC:2711}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING. RX PubMed=9799602; DOI=10.1006/geno.1998.5542; RA Collin G.B., Nishina P.M., Marshall J.D., Naggert J.K.; RT "Human DCTN1: genomic structure and evaluation as a candidate for Alstrom RT syndrome."; RL Genomics 53:359-364(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4). RC TISSUE=Brain, and Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 9-1278. RC TISSUE=Brain; RX PubMed=8838327; DOI=10.1006/geno.1996.0068; RA Holzbaur E.L.F., Tokito M.K.; RT "Localization of the DCTN1 gene encoding p150Glued to human chromosome 2p13 RT by fluorescence in situ hybridization."; RL Genomics 31:398-399(1996). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 9-1278 (ISOFORM 6), AND ALTERNATIVE SPLICING. RC TISSUE=Brain; RX PubMed=8856662; DOI=10.1091/mbc.7.8.1167; RA Tokito M.K., Howland D.S., Lee V.M.-Y., Holzbaur E.L.F.; RT "Functionally distinct isoforms of dynactin are expressed in human RT neurons."; RL Mol. Biol. Cell 7:1167-1180(1996). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 18-1278. RX PubMed=9805007; DOI=10.1016/s0167-4781(98)00195-x; RA Tokito M.K., Holzbaur E.L.F.; RT "The genomic structure of DCTN1, a candidate gene for limb-girdle muscular RT dystrophy."; RL Biochim. Biophys. Acta 1442:432-436(1998). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1081-1278. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [10] RP INTERACTION WITH MAPRE1; MAPRE2 AND MAPRE3. RX PubMed=14514668; DOI=10.1074/jbc.m306194200; RA Bu W., Su L.-K.; RT "Characterization of functional domains of human EB1 family proteins."; RL J. Biol. Chem. 278:49721-49731(2003). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY, AND SUBCELLULAR LOCATION [LARGE SCALE RP ANALYSIS]. RC TISSUE=Lymphoblast; RX PubMed=14654843; DOI=10.1038/nature02166; RA Andersen J.S., Wilkinson C.J., Mayor T., Mortensen P., Nigg E.A., Mann M.; RT "Proteomic characterization of the human centrosome by protein correlation RT profiling."; RL Nature 426:570-574(2003). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [13] RP UBIQUITINATION, AND INTERACTION WITH FBXL5. RX PubMed=17532294; DOI=10.1016/j.bbrc.2007.05.068; RA Zhang N., Liu J., Ding X., Aikhionbare F., Jin C., Yao X.; RT "FBXL5 interacts with p150Glued and regulates its ubiquitination."; RL Biochem. Biophys. Res. Commun. 359:34-39(2007). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [15] RP INTERACTION WITH SNX6. RX PubMed=19935774; DOI=10.1038/cr.2009.130; RA Hong Z., Yang Y., Zhang C., Niu Y., Li K., Zhao X., Liu J.J.; RT "The retromer component SNX6 interacts with dynactin p150(Glued) and RT mediates endosome-to-TGN transport."; RL Cell Res. 19:1334-1349(2009). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-108, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [17] RP INTERACTION WITH ECPAS. RX PubMed=20682791; DOI=10.1074/jbc.m110.154120; RA Gorbea C., Pratt G., Ustrell V., Bell R., Sahasrabudhe S., Hughes R.E., RA Rechsteiner M.; RT "A protein interaction network for Ecm29 links the 26 S proteasome to RT molecular motors and endosomal components."; RL J. Biol. Chem. 285:31616-31633(2010). RN [18] RP INTERACTION WITH PARD6A, AND SUBCELLULAR LOCATION. RX PubMed=20719959; DOI=10.1091/mbc.e10-05-0430; RA Kodani A., Tonthat V., Wu B., Suetterlin C.; RT "Par6 alpha interacts with the dynactin subunit p150 Glued and is a RT critical regulator of centrosomal protein recruitment."; RL Mol. Biol. Cell 21:3376-3385(2010). RN [19] RP INTERACTION WITH DYNAP. RX PubMed=20978158; DOI=10.1158/1535-7163.mct-10-0730; RA Kunoh T., Noda T., Koseki K., Sekigawa M., Takagi M., Shin-ya K., RA Goshima N., Iemura S., Natsume T., Wada S., Mukai Y., Ohta S., Sasaki R., RA Mizukami T.; RT "A novel human dynactin-associated protein, dynAP, promotes activation of RT Akt, and ergosterol-related compounds induce dynAP-dependent apoptosis of RT human cancer cells."; RL Mol. Cancer Ther. 9:2934-2942(2010). RN [20] RP PHOSPHORYLATION AT SER-179 AND SER-212, MUTAGENESIS OF SER-179 AND SER-212, RP INTERACTION WITH PLK1 AND CLIP1, AND SUBCELLULAR LOCATION. RX PubMed=20679239; DOI=10.1073/pnas.1006615107; RA Li H., Liu X.S., Yang X., Song B., Wang Y., Liu X.; RT "Polo-like kinase 1 phosphorylation of p150Glued facilitates nuclear RT envelope breakdown during prophase."; RL Proc. Natl. Acad. Sci. U.S.A. 107:14633-14638(2010). RN [21] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [22] RP INTERACTION WITH DCDC1. RX PubMed=22159412; DOI=10.1242/jcs.085407; RA Kaplan A., Reiner O.; RT "Linking cytoplasmic dynein and transport of Rab8 vesicles to the midbody RT during cytokinesis by the doublecortin domain-containing 5 protein."; RL J. Cell Sci. 124:3989-4000(2011). RN [23] RP INTERACTION WITH CLN3. RX PubMed=22261744; DOI=10.1007/s00018-011-0913-1; RA Uusi-Rauva K., Kyttala A., van der Kant R., Vesa J., Tanhuanpaa K., RA Neefjes J., Olkkonen V.M., Jalanko A.; RT "Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor proteins RT and modifies location of late endosomal compartments."; RL Cell. Mol. Life Sci. 69:2075-2089(2012). RN [24] RP INTERACTION WITH CEP131. RX PubMed=22797915; DOI=10.1242/jcs.104059; RA Staples C.J., Myers K.N., Beveridge R.D., Patil A.A., Lee A.J., Swanton C., RA Howell M., Boulton S.J., Collis S.J.; RT "The centriolar satellite protein Cep131 is important for genome RT stability."; RL J. Cell Sci. 125:4770-4779(2012). RN [25] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=22327364; DOI=10.1038/ncb2440; RA Kiyomitsu T., Cheeseman I.M.; RT "Chromosome- and spindle-pole-derived signals generate an intrinsic code RT for spindle position and orientation."; RL Nat. Cell Biol. 14:311-317(2012). RN [26] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=23386061; DOI=10.1038/emboj.2013.3; RA Kodani A., Salome Sirerol-Piquer M., Seol A., Garcia-Verdugo J.M., RA Reiter J.F.; RT "Kif3a interacts with Dynactin subunit p150 Glued to organize centriole RT subdistal appendages."; RL EMBO J. 32:597-607(2013). RN [27] RP INTERACTION WITH MISP. RX PubMed=23509069; DOI=10.1083/jcb.201207050; RA Zhu M., Settele F., Kotak S., Sanchez-Pulido L., Ehret L., Ponting C.P., RA Goenczy P., Hoffmann I.; RT "MISP is a novel Plk1 substrate required for proper spindle orientation and RT mitotic progression."; RL J. Cell Biol. 200:773-787(2013). RN [28] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [29] RP PHOSPHORYLATION AT THR-145; THR-146 AND THR-147, SUBCELLULAR LOCATION, AND RP MUTAGENESIS OF THR-145; THR-146 AND THR-147. RX PubMed=23985322; DOI=10.1091/mbc.e13-03-0137; RA Zhapparova O.N., Fokin A.I., Vorobyeva N.E., Bryantseva S.A., RA Nadezhdina E.S.; RT "Ste20-like protein kinase SLK (LOSK) regulates microtubule organization by RT targeting dynactin to the centrosome."; RL Mol. Biol. Cell 24:3205-3214(2013). RN [30] RP INTERACTION WITH CEP126. RX PubMed=24867236; DOI=10.1111/boc.201300087; RA Bonavita R., Walas D., Brown A.K., Luini A., Stephens D.J., Colanzi A.; RT "Cep126 is required for pericentriolar satellite localisation to the RT centrosome and for primary cilium formation."; RL Biol. Cell 106:254-267(2014). RN [31] RP INTERACTION WITH HPS6. RX PubMed=25189619; DOI=10.1242/jcs.141978; RA Li K., Yang L., Zhang C., Niu Y., Li W., Liu J.J.; RT "HPS6 interacts with dynactin p150Glued to mediate retrograde trafficking RT and maturation of lysosomes."; RL J. Cell Sci. 127:4574-4588(2014). RN [32] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [33] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=25774020; DOI=10.1002/jcb.25160; RA Chen T.Y., Syu J.S., Han T.Y., Cheng H.L., Lu F.I., Wang C.Y.; RT "Cell cycle-dependent localization of dynactin subunit p150 glued at RT centrosome."; RL J. Cell. Biochem. 116:2049-2060(2015). RN [34] RP ASSOCIATION WITH MICROTUBULES, AND DOMAIN CAP-GLY. RX PubMed=26968983; DOI=10.15252/embj.201593071; RA McKenney R.J., Huynh W., Vale R.D., Sirajuddin M.; RT "Tyrosination of alpha-tubulin controls the initiation of processive RT dynein-dynactin motility."; RL EMBO J. 35:1175-1185(2016). RN [35] RP INTERACTION WITH BCCIP. RX PubMed=28394342; DOI=10.1038/onc.2017.92; RA Huhn S.C., Liu J., Ye C., Lu H., Jiang X., Feng X., Ganesan S., White E., RA Shen Z.; RT "Regulation of spindle integrity and mitotic fidelity by BCCIP."; RL Oncogene 36:4750-4766(2017). RN [36] RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 15-107 IN COMPLEX WITH MAPRE1, RP AND INTERACTION WITH MAPRE1. RX PubMed=16109370; DOI=10.1016/j.molcel.2005.06.034; RA Hayashi I., Wilde A., Mal T.K., Ikura M.; RT "Structural basis for the activation of microtubule assembly by the EB1 and RT p150Glued complex."; RL Mol. Cell 19:449-460(2005). RN [37] RP STRUCTURE BY NMR OF 1-99. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the CAP-Gly domain in human dynactin 1."; RL Submitted (NOV-2005) to the PDB data bank. RN [38] RP X-RAY CRYSTALLOGRAPHY (1.86 ANGSTROMS) OF 18-111 IN COMPLEX WITH MAPRE1, RP AND INTERACTION WITH MAPRE1. RX PubMed=16949363; DOI=10.1016/j.molcel.2006.07.013; RA Honnappa S., Okhrimenko O., Jaussi R., Jawhari H., Jelesarov I., RA Winkler F.K., Steinmetz M.O.; RT "Key interaction modes of dynamic +TIP networks."; RL Mol. Cell 23:663-671(2006). RN [39] RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 15-111 IN COMPLEX WITH CLIP1, RP SUBCELLULAR LOCATION, AND INTERACTION WITH CLIP1. RX PubMed=17828277; DOI=10.1038/nsmb1291; RA Weisbrich A., Honnappa S., Jaussi R., Okhrimenko O., Frey D., Jelesarov I., RA Akhmanova A., Steinmetz M.O.; RT "Structure-function relationship of CAP-Gly domains."; RL Nat. Struct. Mol. Biol. 14:959-967(2007). RN [40] RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 15-107 IN COMPLEX WITH CLIP1, RP INTERACTION WITH CLIP1, AND MUTAGENESIS OF LYS-68 AND ARG-90. RX PubMed=17828275; DOI=10.1038/nsmb1299; RA Hayashi I., Plevin M.J., Ikura M.; RT "CLIP170 autoinhibition mimics intermolecular interactions with p150Glued RT or EB1."; RL Nat. Struct. Mol. Biol. 14:980-981(2007). RN [41] RP VARIANT HMND14 SER-59. RX PubMed=12627231; DOI=10.1038/ng1123; RA Puls I., Jonnakuty C., LaMonte B.H., Holzbaur E.L., Tokito M., Mann E., RA Floeter M.K., Bidus K., Drayna D., Oh S.J., Brown R.H. Jr., Ludlow C.L., RA Fischbeck K.H.; RT "Mutant dynactin in motor neuron disease."; RL Nat. Genet. 33:455-456(2003). RN [42] RP INVOLVEMENT IN ALS, AND VARIANTS ALS THR-571; TRP-785 AND ILE-1249. RX PubMed=15326253; DOI=10.1212/01.wnl.0000134608.83927.b1; RA Muench C., Sedlmeier R., Meyer T., Homberg V., Sperfeld A.D., Kurt A., RA Prudlo J., Peraus G., Hanemann C.O., Stumm G., Ludolph A.C.; RT "Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS."; RL Neurology 63:724-726(2004). RN [43] RP VARIANT ALS LYS-1101. RX PubMed=16240349; DOI=10.1002/ana.20631; RA Muench C., Rosenbohm A., Sperfeld A.-D., Uttner I., Reske S., Krause B.J., RA Sedlmeier R., Meyer T., Hanemann C.O., Stumm G., Ludolph A.C.; RT "Heterozygous R1101K mutation of the DCTN1 gene in a family with ALS and RT FTD."; RL Ann. Neurol. 58:777-780(2005). RN [44] RP CHARACTERIZATION OF VARIANT HMND14 SER-59, AND INTERACTION WITH MAPRE1. RX PubMed=16505168; DOI=10.1083/jcb.200511068; RA Levy J.R., Sumner C.J., Caviston J.P., Tokito M.K., Ranganathan S., RA Ligon L.A., Wallace K.E., LaMonte B.H., Harmison G.G., Puls I., RA Fischbeck K.H., Holzbaur E.L.F.; RT "A motor neuron disease-associated mutation in p150Glued perturbs dynactin RT function and induces protein aggregation."; RL J. Cell Biol. 172:733-745(2006). RN [45] RP VARIANTS VAL-196; GLN-495 AND ILE-1249. RX PubMed=17824900; DOI=10.1111/j.1600-0404.2007.00884.x; RA Muench C., Meyer R., Linke P., Meyer T., Ludolph A.C., Haas J., Hemmer B.; RT "The p150 subunit of dynactin (DCTN1) gene in multiple sclerosis."; RL Acta Neurol. Scand. 116:231-234(2007). RN [46] RP VARIANTS PERRYS ARG-71; GLU-71; ALA-71; PRO-72 AND PRO-74, CHARACTERIZATION RP OF VARIANTS PERRYS ARG-71 AND PRO-74, AND CHARACTERIZATION OF VARIANT RP HMND14 SER-59. RX PubMed=19136952; DOI=10.1038/ng.293; RA Farrer M.J., Hulihan M.M., Kachergus J.M., Daechsel J.C., Stoessl A.J., RA Grantier L.L., Calne S., Calne D.B., Lechevalier B., Chapon F., Tsuboi Y., RA Yamada T., Gutmann L., Elibol B., Bhatia K.P., Wider C., RA Vilarino-Gueell C., Ross O.A., Brown L.A., Castanedes-Casey M., RA Dickson D.W., Wszolek Z.K.; RT "DCTN1 mutations in Perry syndrome."; RL Nat. Genet. 41:163-165(2009). RN [47] RP VARIANT ILE-1249. RX PubMed=19506225; DOI=10.1212/wnl.0b013e3181a92c4c; RA Vilarino-Gueell C., Wider C., Soto-Ortolaza A.I., Cobb S.A., RA Kachergus J.M., Keeling B.H., Dachsel J.C., Hulihan M.M., Dickson D.W., RA Wszolek Z.K., Uitti R.J., Graff-Radford N.R., Boeve B.F., Josephs K.A., RA Miller B., Boylan K.B., Gwinn K., Adler C.H., Aasly J.O., Hentati F., RA Destee A., Krygowska-Wajs A., Chartier-Harlin M.-C., Ross O.A., RA Rademakers R., Farrer M.J.; RT "Characterization of DCTN1 genetic variability in neurodegeneration."; RL Neurology 72:2024-2028(2009). RN [48] RP CHARACTERIZATION OF VARIANT HMND14 SER-59. RX PubMed=19279216; DOI=10.1073/pnas.0810828106; RA Moore J.K., Sept D., Cooper J.A.; RT "Neurodegeneration mutations in dynactin impair dynein-dependent nuclear RT migration."; RL Proc. Natl. Acad. Sci. U.S.A. 106:5147-5152(2009). RN [49] RP CHARACTERIZATION OF VARIANT HMND14 SER-59, CHARACTERIZATION OF VARIANT RP 196-ILE, INTERACTION WITH TBCB, AND SUBCELLULAR LOCATION. RX PubMed=22777741; DOI=10.1007/s00441-012-1463-z; RA Kuh G.F., Stockmann M., Meyer-Ohlendorf M., Linta L., Proepper C., RA Ludolph A.C., Bockmann J., Boeckers T.M., Liebau S.; RT "Tubulin-binding cofactor B is a direct interaction partner of the dynactin RT subunit p150(Glued)."; RL Cell Tissue Res. 350:13-26(2012). RN [50] RP CHARACTERIZATION OF VARIANT PERRYS PRO-74, FUNCTION, SUBUNIT, AND RP INTERACTION WITH MAPRE1. RX PubMed=23874158; DOI=10.1371/journal.pbio.1001611; RA Lazarus J.E., Moughamian A.J., Tokito M.K., Holzbaur E.L.; RT "Dynactin subunit p150(Glued) is a neuron-specific anti-catastrophe RT factor."; RL PLoS Biol. 11:E1001611-E1001611(2013). RN [51] RP VARIANT PHE-670. RX PubMed=24627108; DOI=10.1007/s00415-014-7289-8; RA Schabhuettl M., Wieland T., Senderek J., Baets J., Timmerman V., RA De Jonghe P., Reilly M.M., Stieglbauer K., Laich E., Windhager R., Erwa W., RA Trajanoski S., Strom T.M., Auer-Grumbach M.; RT "Whole-exome sequencing in patients with inherited neuropathies: outcome RT and challenges."; RL J. Neurol. 261:970-982(2014). RN [52] RP VARIANT PERRYS LEU-52. RX PubMed=24676999; DOI=10.1002/mds.25833; RA Araki E., Tsuboi Y., Daechsel J., Milnerwood A., Vilarino-Guell C., RA Fujii N., Mishima T., Oka T., Hara H., Fukae J., Farrer M.J.; RT "A Novel DCTN1 mutation with late-onset parkinsonism and frontotemporal RT atrophy."; RL Mov. Disord. 29:1201-1204(2014). RN [53] RP CHARACTERIZATION OF VARIANTS PERRYS ARG-71 AND PRO-74, FUNCTION, RP INTERACTION WITH DYNEIN INTERMEDIATE CHAIN AND DYNEIN HEAVY CHAIN, AND RP DOMAIN CAP-GLY. RX PubMed=25185702; DOI=10.1038/ncomms5807; RA Ayloo S., Lazarus J.E., Dodda A., Tokito M., Ostap E.M., Holzbaur E.L.; RT "Dynactin functions as both a dynamic tether and brake during dynein-driven RT motility."; RL Nat. Commun. 5:4807-4807(2014). RN [54] RP VARIANTS PERRYS ARG-71 AND CYS-78, AND CHARACTERIZATION OF VARIANTS PERRYS RP ARG-71 AND CYS-78. RX PubMed=24881494; DOI=10.1016/j.parkreldis.2014.05.004; RA Tacik P., Fiesel F.C., Fujioka S., Ross O.A., Pretelt F., RA Castaneda Cardona C., Kidd A., Hlavac M., Raizis A., Okun M.S., Traynor S., RA Strongosky A.J., Springer W., Wszolek Z.K.; RT "Three families with Perry syndrome from distinct parts of the world."; RL Parkinsonism Relat. Disord. 20:884-888(2014). RN [55] RP CHARACTERIZATION OF VARIANT PERRYS ARG-71, SUBCELLULAR LOCATION, DOMAIN RP CAP-GLY, INTERACTION WITH CLIP1, AND ASSOCIATION WITH MICROTUBULES. RX PubMed=26972003; DOI=10.1016/j.celrep.2016.02.046; RA Nirschl J.J., Magiera M.M., Lazarus J.E., Janke C., Holzbaur E.L.; RT "Alpha-tubulin tyrosination and CLIP-170 phosphorylation regulate the RT initiation of dynein-driven transport in neurons."; RL Cell Rep. 14:2637-2652(2016). RN [56] RP INTERACTION WITH RUFY3 AND RUFY4. RX PubMed=35314674; DOI=10.1038/s41467-022-28952-y; RA Keren-Kaplan T., Saric A., Ghosh S., Williamson C.D., Jia R., Li Y., RA Bonifacino J.S.; RT "RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes RT to dynein-dynactin."; RL Nat. Commun. 13:1506-1506(2022). CC -!- FUNCTION: Part of the dynactin complex that activates the molecular CC motor dynein for ultra-processive transport along microtubules (By CC similarity). Plays a key role in dynein-mediated retrograde transport CC of vesicles and organelles along microtubules by recruiting and CC tethering dynein to microtubules. Binds to both dynein and microtubules CC providing a link between specific cargos, microtubules and dynein. CC Essential for targeting dynein to microtubule plus ends, recruiting CC dynein to membranous cargos and enhancing dynein processivity (the CC ability to move along a microtubule for a long distance without falling CC off the track). Can also act as a brake to slow the dynein motor during CC motility along the microtubule (PubMed:25185702). Can regulate CC microtubule stability by promoting microtubule formation, nucleation CC and polymerization and by inhibiting microtubule catastrophe in CC neurons. Inhibits microtubule catastrophe by binding both to CC microtubules and to tubulin, leading to enhanced microtubule stability CC along the axon (PubMed:23874158). Plays a role in metaphase spindle CC orientation (PubMed:22327364). Plays a role in centriole cohesion and CC subdistal appendage organization and function. Its recruitment to the CC centriole in a KIF3A-dependent manner is essential for the maintenance CC of centriole cohesion and the formation of subdistal appendage. Also CC required for microtubule anchoring at the mother centriole CC (PubMed:23386061). Plays a role in primary cilia formation CC (PubMed:25774020). {ECO:0000250|UniProtKB:A0A287B8J2, CC ECO:0000269|PubMed:22327364, ECO:0000269|PubMed:23386061, CC ECO:0000269|PubMed:23874158, ECO:0000269|PubMed:25185702, CC ECO:0000269|PubMed:25774020}. CC -!- SUBUNIT: Monomer and homodimer (PubMed:23874158). Subunit of dynactin, CC a multiprotein complex part of a tripartite complex with dynein and a CC adapter, such as BICDL1, BICD2 or HOOK3. The dynactin complex is built CC around ACTR1A/ACTB filament and consists of an actin-related filament CC composed of a shoulder domain, a pointed end and a barbed end. Its CC length is defined by its flexible shoulder domain. The soulder is CC composed of 2 DCTN1 subunits, 4 DCTN2 and 2 DCTN3. DCTN1/p150(glued) CC binds directly to microtubules and to cytoplasmic dynein. The 4 DCNT2 CC (via N-terminus) bind the ACTR1A filament and act as molecular rulers CC to determine the length. The pointed end is important for binding CC dynein-dynactin cargo adapters. Consists of 4 subunits: ACTR10, DCNT4, CC DCTN5 and DCTN6. The barbed end is composed of a CAPZA1:CAPZB CC heterodimers, which binds ACTR1A/ACTB filament and dynactin and CC stabilizes dynactin (By similarity). Interacts with the C-terminus of CC MAPRE1, MAPRE2 and MAPRE3. Interacts (via C-terminus) with SNX6. CC Interacts with CLN3, DYNAP, ECPAS and FBXL5. Interacts with MISP; this CC interaction regulates its distribution at the cell cortex. Interacts CC with CEP131. Interacts with CEP126 (PubMed:24867236). Interacts with CC CLIP1 (PubMed:17828275, PubMed:17828277, PubMed:20679239, CC PubMed:26972003). Interacts with dynein intermediate chain and dynein CC heavy chain (PubMed:25185702). Interacts with PLK1 (via POLO-box CC domain) (PubMed:20679239). Interacts with TBCB (PubMed:22777741). Binds CC preferentially to tyrosinated microtubules than to detyrosinated CC microtubules (PubMed:26968983, PubMed:26972003). Interacts with PARD6A CC (PubMed:20719959). Interacts with HPS6 (PubMed:25189619). Interacts CC with KIF3A. Interacts with BICD2 (By similarity). Interacts with DST CC (isoform 9) (By similarity). Interacts with DST (isoform 1) (By CC similarity). Identified in a complex with MREG and RILP (By CC similarity). Interacts with BCCIP (isoform 2/alpha) (PubMed:28394342). CC Interacts with DCDC1 (PubMed:22159412). Interacts with AKNA (By CC similarity). Interacts with DYNC1I2 (By similarity). Interacts with CC RUFY3 and RUFY4 (PubMed:35314674). {ECO:0000250|UniProtKB:A0A287B8J2, CC ECO:0000250|UniProtKB:O08788, ECO:0000269|PubMed:14514668, CC ECO:0000269|PubMed:16109370, ECO:0000269|PubMed:16505168, CC ECO:0000269|PubMed:16949363, ECO:0000269|PubMed:17532294, CC ECO:0000269|PubMed:17828275, ECO:0000269|PubMed:17828277, CC ECO:0000269|PubMed:19935774, ECO:0000269|PubMed:20679239, CC ECO:0000269|PubMed:20682791, ECO:0000269|PubMed:20719959, CC ECO:0000269|PubMed:20978158, ECO:0000269|PubMed:22159412, CC ECO:0000269|PubMed:22261744, ECO:0000269|PubMed:22777741, CC ECO:0000269|PubMed:22797915, ECO:0000269|PubMed:23509069, CC ECO:0000269|PubMed:23874158, ECO:0000269|PubMed:24867236, CC ECO:0000269|PubMed:25185702, ECO:0000269|PubMed:25189619, CC ECO:0000269|PubMed:26968983, ECO:0000269|PubMed:26972003, CC ECO:0000269|PubMed:28394342, ECO:0000269|PubMed:35314674}. CC -!- INTERACTION: CC Q14203; Q9NZ32: ACTR10; NbExp=7; IntAct=EBI-724352, EBI-2559426; CC Q14203; P61163: ACTR1A; NbExp=8; IntAct=EBI-724352, EBI-774234; CC Q14203; P42025: ACTR1B; NbExp=6; IntAct=EBI-724352, EBI-367493; CC Q14203; Q96RK4: BBS4; NbExp=3; IntAct=EBI-724352, EBI-1805814; CC Q14203; P52907: CAPZA1; NbExp=3; IntAct=EBI-724352, EBI-355586; CC Q14203; P47756: CAPZB; NbExp=7; IntAct=EBI-724352, EBI-353595; CC Q14203; P30622-1: CLIP1; NbExp=7; IntAct=EBI-724352, EBI-9640673; CC Q14203; Q13561: DCTN2; NbExp=9; IntAct=EBI-724352, EBI-715074; CC Q14203; O75935: DCTN3; NbExp=7; IntAct=EBI-724352, EBI-347442; CC Q14203; Q9UJW0: DCTN4; NbExp=7; IntAct=EBI-724352, EBI-2134033; CC Q14203; O00399: DCTN6; NbExp=9; IntAct=EBI-724352, EBI-2559415; CC Q14203; Q15691: MAPRE1; NbExp=9; IntAct=EBI-724352, EBI-1004115; CC Q14203; P10636-8: MAPT; NbExp=9; IntAct=EBI-724352, EBI-366233; CC Q14203; Q9UNH7: SNX6; NbExp=2; IntAct=EBI-724352, EBI-949294; CC Q14203; P54256: Hap1; Xeno; NbExp=4; IntAct=EBI-724352, EBI-994539; CC Q14203-5; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-25840379, EBI-25840993; CC Q14203-5; P63010-2: AP2B1; NbExp=3; IntAct=EBI-25840379, EBI-11529439; CC Q14203-5; P05067: APP; NbExp=5; IntAct=EBI-25840379, EBI-77613; CC Q14203-5; O95671: ASMTL; NbExp=3; IntAct=EBI-25840379, EBI-743231; CC Q14203-5; P18847: ATF3; NbExp=3; IntAct=EBI-25840379, EBI-712767; CC Q14203-5; P46379-2: BAG6; NbExp=3; IntAct=EBI-25840379, EBI-10988864; CC Q14203-5; Q8NFJ9: BBS1; NbExp=3; IntAct=EBI-25840379, EBI-1805484; CC Q14203-5; O15392: BIRC5; NbExp=3; IntAct=EBI-25840379, EBI-518823; CC Q14203-5; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-25840379, EBI-2837444; CC Q14203-5; P42574: CASP3; NbExp=3; IntAct=EBI-25840379, EBI-524064; CC Q14203-5; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-25840379, EBI-350590; CC Q14203-5; O75935-2: DCTN3; NbExp=3; IntAct=EBI-25840379, EBI-12091947; CC Q14203-5; O60479: DLX3; NbExp=3; IntAct=EBI-25840379, EBI-3908248; CC Q14203-5; O14576-2: DYNC1I1; NbExp=3; IntAct=EBI-25840379, EBI-25840445; CC Q14203-5; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-25840379, EBI-9246952; CC Q14203-5; Q6NXG1: ESRP1; NbExp=3; IntAct=EBI-25840379, EBI-10213520; CC Q14203-5; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-25840379, EBI-396453; CC Q14203-5; Q9UBN7: HDAC6; NbExp=6; IntAct=EBI-25840379, EBI-301697; CC Q14203-5; Q8IY31-3: IFT20; NbExp=3; IntAct=EBI-25840379, EBI-9091197; CC Q14203-5; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-25840379, EBI-21911304; CC Q14203-5; Q96EK5: KIFBP; NbExp=3; IntAct=EBI-25840379, EBI-744150; CC Q14203-5; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-25840379, EBI-714379; CC Q14203-5; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-25840379, EBI-11985629; CC Q14203-5; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-25840379, EBI-1108377; CC Q14203-5; O95777: LSM8; NbExp=3; IntAct=EBI-25840379, EBI-347779; CC Q14203-5; P43360: MAGEA6; NbExp=3; IntAct=EBI-25840379, EBI-1045155; CC Q14203-5; P10636-6: MAPT; NbExp=3; IntAct=EBI-25840379, EBI-7796455; CC Q14203-5; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-25840379, EBI-21250407; CC Q14203-5; Q8N594: MPND; NbExp=3; IntAct=EBI-25840379, EBI-2512452; CC Q14203-5; O15381-5: NVL; NbExp=3; IntAct=EBI-25840379, EBI-18577082; CC Q14203-5; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-25840379, EBI-1058491; CC Q14203-5; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-25840379, EBI-25830200; CC Q14203-5; Q9BR81: PCDHGC3; NbExp=3; IntAct=EBI-25840379, EBI-22012354; CC Q14203-5; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-25840379, EBI-6309018; CC Q14203-5; P17980: PSMC3; NbExp=3; IntAct=EBI-25840379, EBI-359720; CC Q14203-5; Q9UJ41-4: RABGEF1; NbExp=3; IntAct=EBI-25840379, EBI-14093916; CC Q14203-5; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-25840379, EBI-25829984; CC Q14203-5; Q8IYW5: RNF168; NbExp=3; IntAct=EBI-25840379, EBI-914207; CC Q14203-5; Q96D59: RNF183; NbExp=3; IntAct=EBI-25840379, EBI-743938; CC Q14203-5; Q92834-6: RPGR; NbExp=3; IntAct=EBI-25840379, EBI-16431517; CC Q14203-5; Q8N488: RYBP; NbExp=3; IntAct=EBI-25840379, EBI-752324; CC Q14203-5; Q15436: SEC23A; NbExp=3; IntAct=EBI-25840379, EBI-81088; CC Q14203-5; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-25840379, EBI-358545; CC Q14203-5; Q9HCE7-2: SMURF1; NbExp=3; IntAct=EBI-25840379, EBI-9845742; CC Q14203-5; Q99932-2: SPAG8; NbExp=3; IntAct=EBI-25840379, EBI-11959123; CC Q14203-5; O75886: STAM2; NbExp=3; IntAct=EBI-25840379, EBI-373258; CC Q14203-5; Q15554-4: TERF2; NbExp=3; IntAct=EBI-25840379, EBI-25840535; CC Q14203-5; Q71RG4-4: TMUB2; NbExp=3; IntAct=EBI-25840379, EBI-25831574; CC Q14203-5; Q9H0E2: TOLLIP; NbExp=3; IntAct=EBI-25840379, EBI-74615; CC Q14203-5; P19474: TRIM21; NbExp=3; IntAct=EBI-25840379, EBI-81290; CC Q14203-5; Q8WVJ9: TWIST2; NbExp=3; IntAct=EBI-25840379, EBI-1797313; CC Q14203-5; P62987: UBA52; NbExp=3; IntAct=EBI-25840379, EBI-357304; CC Q14203-5; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-25840379, EBI-749370; CC Q14203-5; Q8NBM4-4: UBAC2; NbExp=3; IntAct=EBI-25840379, EBI-25840976; CC Q14203-5; P57075-2: UBASH3A; NbExp=3; IntAct=EBI-25840379, EBI-7353612; CC Q14203-5; Q04323-2: UBXN1; NbExp=3; IntAct=EBI-25840379, EBI-11530712; CC Q14203-5; Q96RL1-2: UIMC1; NbExp=3; IntAct=EBI-25840379, EBI-17761788; CC Q14203-5; O00308: WWP2; NbExp=3; IntAct=EBI-25840379, EBI-743923; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17828277}. CC Cytoplasm, cytoskeleton {ECO:0000269|PubMed:17828277, CC ECO:0000269|PubMed:22777741, ECO:0000269|PubMed:25774020, CC ECO:0000269|PubMed:26972003}. Cytoplasm, cytoskeleton, microtubule CC organizing center, centrosome {ECO:0000269|PubMed:14654843, CC ECO:0000269|PubMed:20719959, ECO:0000269|PubMed:23985322, CC ECO:0000269|PubMed:25774020}. Cytoplasm, cytoskeleton, microtubule CC organizing center, centrosome, centriole {ECO:0000269|PubMed:23386061, CC ECO:0000269|PubMed:25774020}. Cytoplasm, cytoskeleton, spindle CC {ECO:0000269|PubMed:25774020}. Nucleus envelope CC {ECO:0000269|PubMed:20679239}. Cytoplasm, cell cortex CC {ECO:0000269|PubMed:22327364}. Note=Localizes to microtubule plus ends CC (PubMed:17828277, PubMed:22777741, PubMed:25774020). Localizes CC preferentially to the ends of tyrosinated microtubules CC (PubMed:26972003). Localization at centrosome is regulated by SLK- CC dependent phosphorylation (PubMed:23985322). Localizes to centrosome in CC a PARKDA-dependent manner (PubMed:20719959). Localizes to the subdistal CC appendage region of the centriole in a KIF3A-dependent manner CC (PubMed:23386061). PLK1-mediated phosphorylation at Ser-179 is CC essential for its localization in the nuclear envelope CC (PubMed:20679239). {ECO:0000269|PubMed:17828277, CC ECO:0000269|PubMed:20679239, ECO:0000269|PubMed:20719959, CC ECO:0000269|PubMed:22777741, ECO:0000269|PubMed:23386061, CC ECO:0000269|PubMed:23985322, ECO:0000269|PubMed:25774020, CC ECO:0000269|PubMed:26972003}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=p150; CC IsoId=Q14203-1; Sequence=Displayed; CC Name=p135; CC IsoId=Q14203-2; Sequence=VSP_000760; CC Name=3; CC IsoId=Q14203-3; Sequence=VSP_045392, VSP_045393, VSP_045394; CC Name=4; CC IsoId=Q14203-4; Sequence=VSP_045393, VSP_045394; CC Name=5; CC IsoId=Q14203-5; Sequence=VSP_000760, VSP_045394; CC Name=6; CC IsoId=Q14203-6; Sequence=VSP_047174; CC -!- TISSUE SPECIFICITY: Brain. CC -!- DOMAIN: The CAP-Gly domain is essential for interactions with CC microtubules and its binding partners and for its motion along the CC microtubules. Essential for its preferential binding to tyrosinated CC microtubules and for promoting the sustained interaction of the dynein CC motor with microtubules. {ECO:0000269|PubMed:25185702, CC ECO:0000269|PubMed:26968983, ECO:0000269|PubMed:26972003}. CC -!- PTM: Ubiquitinated by a SCF complex containing FBXL5, leading to its CC degradation by the proteasome. {ECO:0000269|PubMed:17532294}. CC -!- PTM: Phosphorylation by SLK at Thr-145, Thr-146 and Thr-147 targets CC DCTN1 to the centrosome. It is uncertain if SLK phosphorylates all CC three threonines or one or two of them. PLK1-mediated phosphorylation CC at Ser-179 is essential for its localization in the nuclear envelope, CC promotes its dissociation from microtubules during early mitosis and CC positively regulates nuclear envelope breakdown during prophase. CC {ECO:0000269|PubMed:20679239, ECO:0000269|PubMed:23985322}. CC -!- DISEASE: Neuronopathy, distal hereditary motor, autosomal dominant 14 CC (HMND14) [MIM:607641]: A form of distal hereditary motor neuronopathy, CC a heterogeneous group of neuromuscular disorders caused by selective CC degeneration of motor neurons in the anterior horn of the spinal cord, CC without sensory deficit in the posterior horn. The overall clinical CC picture consists of a classical distal muscular atrophy syndrome in the CC legs without clinical sensory loss. The disease starts with weakness CC and wasting of distal muscles of the anterior tibial and peroneal CC compartments of the legs. Later on, weakness and atrophy may expand to CC the proximal muscles of the lower limbs and/or to the distal upper CC limbs. {ECO:0000269|PubMed:12627231, ECO:0000269|PubMed:16505168, CC ECO:0000269|PubMed:19136952, ECO:0000269|PubMed:19279216, CC ECO:0000269|PubMed:22777741}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Amyotrophic lateral sclerosis (ALS) [MIM:105400]: A CC neurodegenerative disorder affecting upper motor neurons in the brain CC and lower motor neurons in the brain stem and spinal cord, resulting in CC fatal paralysis. Sensory abnormalities are absent. The pathologic CC hallmarks of the disease include pallor of the corticospinal tract due CC to loss of motor neurons, presence of ubiquitin-positive inclusions CC within surviving motor neurons, and deposition of pathologic CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to CC be multifactorial, involving both genetic and environmental factors. CC The disease is inherited in 5-10% of the cases. CC {ECO:0000269|PubMed:15326253, ECO:0000269|PubMed:16240349}. CC Note=Disease susceptibility is associated with variants affecting the CC gene represented in this entry. CC -!- DISEASE: Perry syndrome (PERRYS) [MIM:168605]: A neuropsychiatric CC disorder characterized by mental depression not responsive to CC antidepressant drugs or electroconvulsive therapy, sleep disturbances, CC exhaustion and marked weight loss. Parkinsonism develops later and CC respiratory failure occurred terminally. {ECO:0000269|PubMed:19136952, CC ECO:0000269|PubMed:23874158, ECO:0000269|PubMed:24676999, CC ECO:0000269|PubMed:24881494, ECO:0000269|PubMed:25185702, CC ECO:0000269|PubMed:26972003}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the dynactin 150 kDa subunit family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF064205; AAD55811.1; -; Genomic_DNA. DR EMBL; AF064203; AAD55811.1; JOINED; Genomic_DNA. DR EMBL; AF064204; AAD55811.1; JOINED; Genomic_DNA. DR EMBL; AF064205; AAD55812.1; -; Genomic_DNA. DR EMBL; AF064204; AAD55812.1; JOINED; Genomic_DNA. DR EMBL; AK297286; BAG59757.1; -; mRNA. DR EMBL; AK314352; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AC005041; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471053; EAW99684.1; -; Genomic_DNA. DR EMBL; BC071583; AAH71583.1; -; mRNA. DR EMBL; X98801; CAA67333.1; -; mRNA. DR EMBL; AF086947; AAD03694.1; -; Genomic_DNA. DR EMBL; AF086927; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086928; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086929; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086930; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086931; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086932; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086933; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086934; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086935; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086936; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086937; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086938; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086939; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086940; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086941; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086942; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086943; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086944; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086945; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086946; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; BT006758; AAP35404.1; -; mRNA. DR CCDS; CCDS1939.1; -. [Q14203-1] DR CCDS; CCDS46341.1; -. [Q14203-4] DR CCDS; CCDS46342.1; -. [Q14203-5] DR CCDS; CCDS46343.1; -. [Q14203-2] DR CCDS; CCDS54368.1; -. [Q14203-3] DR CCDS; CCDS54369.1; -. [Q14203-6] DR RefSeq; NP_001128512.1; NM_001135040.3. [Q14203-4] DR RefSeq; NP_001128513.1; NM_001135041.3. [Q14203-5] DR RefSeq; NP_001177765.1; NM_001190836.2. [Q14203-3] DR RefSeq; NP_001177766.1; NM_001190837.2. [Q14203-6] DR RefSeq; NP_004073.2; NM_004082.4. [Q14203-1] DR RefSeq; NP_075408.1; NM_023019.4. [Q14203-2] DR PDB; 1TXQ; X-ray; 1.80 A; A=15-107. DR PDB; 2COY; NMR; -; A=1-99. DR PDB; 2HKN; X-ray; 1.87 A; A/B=18-111. DR PDB; 2HKQ; X-ray; 1.86 A; B=18-111. DR PDB; 2HL3; X-ray; 2.03 A; A/B=18-111. DR PDB; 2HL5; X-ray; 1.93 A; C/D=18-111. DR PDB; 2HQH; X-ray; 1.80 A; A/B/C/D=15-107. DR PDB; 3E2U; X-ray; 2.60 A; A/B/C/D=18-111. DR PDB; 3TQ7; X-ray; 2.30 A; P/Q=27-97. DR PDB; 9B7J; EM; 3.49 A; S/s=1-1278. DR PDBsum; 1TXQ; -. DR PDBsum; 2COY; -. DR PDBsum; 2HKN; -. DR PDBsum; 2HKQ; -. DR PDBsum; 2HL3; -. DR PDBsum; 2HL5; -. DR PDBsum; 2HQH; -. DR PDBsum; 3E2U; -. DR PDBsum; 3TQ7; -. DR PDBsum; 9B7J; -. DR AlphaFoldDB; Q14203; -. DR BMRB; Q14203; -. DR EMDB; EMD-2673; -. DR EMDB; EMD-2674; -. DR EMDB; EMD-2675; -. DR EMDB; EMD-44306; -. DR SMR; Q14203; -. DR BioGRID; 108007; 502. DR ComplexPortal; CPX-26352; Dynactin complex. DR CORUM; Q14203; -. DR DIP; DIP-31365N; -. DR FunCoup; Q14203; 1563. DR IntAct; Q14203; 326. DR MINT; Q14203; -. DR STRING; 9606.ENSP00000354791; -. DR CarbonylDB; Q14203; -. DR GlyCosmos; Q14203; 1 site, 1 glycan. DR GlyGen; Q14203; 3 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q14203; -. DR MetOSite; Q14203; -. DR PhosphoSitePlus; Q14203; -. DR SwissPalm; Q14203; -. DR BioMuta; DCTN1; -. DR DMDM; 17375490; -. DR OGP; Q14203; -. DR jPOST; Q14203; -. DR MassIVE; Q14203; -. DR PaxDb; 9606-ENSP00000354791; -. DR PeptideAtlas; Q14203; -. DR ProteomicsDB; 20166; -. DR ProteomicsDB; 20302; -. DR ProteomicsDB; 2371; -. DR ProteomicsDB; 33940; -. DR ProteomicsDB; 59925; -. [Q14203-1] DR ProteomicsDB; 59926; -. [Q14203-2] DR Pumba; Q14203; -. DR ABCD; Q14203; 1 sequenced antibody. DR Antibodypedia; 3966; 328 antibodies from 41 providers. DR DNASU; 1639; -. DR Ensembl; ENST00000394003.7; ENSP00000377571.3; ENSG00000204843.14. [Q14203-6] DR Ensembl; ENST00000409240.5; ENSP00000386406.1; ENSG00000204843.14. [Q14203-3] DR Ensembl; ENST00000409438.5; ENSP00000387270.1; ENSG00000204843.14. [Q14203-5] DR Ensembl; ENST00000409567.7; ENSP00000386843.3; ENSG00000204843.14. [Q14203-4] DR Ensembl; ENST00000628224.3; ENSP00000487279.2; ENSG00000204843.14. [Q14203-1] DR Ensembl; ENST00000633691.1; ENSP00000487724.1; ENSG00000204843.14. [Q14203-2] DR GeneID; 1639; -. DR KEGG; hsa:1639; -. DR MANE-Select; ENST00000628224.3; ENSP00000487279.2; NM_004082.5; NP_004073.2. DR UCSC; uc002sku.4; human. [Q14203-1] DR AGR; HGNC:2711; -. DR ClinPGx; PA27180; -. DR CTD; 1639; -. DR DisGeNET; 1639; -. DR GeneCards; DCTN1; -. DR GeneReviews; DCTN1; -. DR HGNC; HGNC:2711; DCTN1. DR HPA; ENSG00000204843; Low tissue specificity. DR MalaCards; DCTN1; -. DR MIM; 105400; phenotype. DR MIM; 168605; phenotype. DR MIM; 601143; gene. DR MIM; 607641; phenotype. DR OpenTargets; ENSG00000204843; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 139589; Distal hereditary motor neuropathy type 7. DR Orphanet; 178509; Perry syndrome. DR VEuPathDB; HostDB:ENSG00000204843; -. DR eggNOG; KOG0971; Eukaryota. DR GeneTree; ENSGT00940000155378; -. DR HOGENOM; CLU_002523_0_0_1; -. DR InParanoid; Q14203; -. DR OMA; LFEMEPV; -. DR OrthoDB; 2130750at2759; -. DR PAN-GO; Q14203; 11 GO annotations based on evolutionary models. DR PhylomeDB; Q14203; -. DR PathwayCommons; Q14203; -. DR Reactome; R-HSA-2132295; MHC class II antigen presentation. DR Reactome; R-HSA-2565942; Regulation of PLK1 Activity at G2/M Transition. [Q14203-2] DR Reactome; R-HSA-3371497; HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand. DR Reactome; R-HSA-380259; Loss of Nlp from mitotic centrosomes. [Q14203-2] DR Reactome; R-HSA-380270; Recruitment of mitotic centrosome proteins and complexes. [Q14203-2] DR Reactome; R-HSA-380284; Loss of proteins required for interphase microtubule organization from the centrosome. [Q14203-2] DR Reactome; R-HSA-380320; Recruitment of NuMA to mitotic centrosomes. [Q14203-2] DR Reactome; R-HSA-381038; XBP1(S) activates chaperone genes. DR Reactome; R-HSA-5620912; Anchoring of the basal body to the plasma membrane. [Q14203-2] DR Reactome; R-HSA-6807878; COPI-mediated anterograde transport. DR Reactome; R-HSA-6811436; COPI-independent Golgi-to-ER retrograde traffic. DR Reactome; R-HSA-8854518; AURKA Activation by TPX2. [Q14203-2] DR Reactome; R-HSA-9725370; Signaling by ALK fusions and activated point mutants. DR SignaLink; Q14203; -. DR SIGNOR; Q14203; -. DR Agora; ENSG00000204843; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 1639; 273 hits in 1160 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; DCTN1; human. DR EvolutionaryTrace; Q14203; -. DR GeneWiki; DCTN1; -. DR GenomeRNAi; 1639; -. DR Pharos; Q14203; Tbio. DR PRO; PR:Q14203; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q14203; protein. DR Bgee; ENSG00000204843; Expressed in right frontal lobe and 192 other cell types or tissues. DR ExpressionAtlas; Q14203; baseline and differential. DR GO; GO:0001669; C:acrosomal vesicle; IDA:HPA. DR GO; GO:0030424; C:axon; IBA:GO_Central. DR GO; GO:0005938; C:cell cortex; IDA:UniProtKB. DR GO; GO:0099738; C:cell cortex region; IDA:UniProtKB. DR GO; GO:0031252; C:cell leading edge; IEA:Ensembl. DR GO; GO:0120103; C:centriolar subdistal appendage; IDA:GO_Central. DR GO; GO:0005814; C:centriole; IDA:UniProtKB. DR GO; GO:0005813; C:centrosome; IDA:UniProtKB. DR GO; GO:0036064; C:ciliary basal body; IDA:HPA. DR GO; GO:0005929; C:cilium; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IDA:ARUK-UCL. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0030286; C:dynein complex; IEA:UniProtKB-KW. DR GO; GO:0045171; C:intercellular bridge; IDA:HPA. DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005874; C:microtubule; IDA:UniProtKB. DR GO; GO:0005875; C:microtubule associated complex; IMP:ARUK-UCL. DR GO; GO:0015630; C:microtubule cytoskeleton; IDA:HPA. DR GO; GO:0035371; C:microtubule plus-end; IDA:UniProtKB. DR GO; GO:0072686; C:mitotic spindle; IDA:HPA. DR GO; GO:0043005; C:neuron projection; IDA:ARUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IDA:ARUK-UCL. DR GO; GO:0005635; C:nuclear envelope; IDA:UniProtKB. DR GO; GO:0033011; C:perinuclear theca; IDA:HPA. DR GO; GO:0005819; C:spindle; IDA:UniProtKB. DR GO; GO:0000922; C:spindle pole; IDA:UniProtKB. DR GO; GO:0008017; F:microtubule binding; IDA:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IPI:ARUK-UCL. DR GO; GO:0048156; F:tau protein binding; NAS:ARUK-UCL. DR GO; GO:0015631; F:tubulin binding; IDA:UniProtKB. DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW. DR GO; GO:0010457; P:centriole-centriole cohesion; IMP:UniProtKB. DR GO; GO:0000132; P:establishment of mitotic spindle orientation; IMP:UniProtKB. DR GO; GO:0099558; P:maintenance of synapse structure; TAS:ARUK-UCL. DR GO; GO:0032402; P:melanosome transport; IEA:Ensembl. DR GO; GO:0034454; P:microtubule anchoring at centrosome; IMP:UniProtKB. DR GO; GO:0000278; P:mitotic cell cycle; NAS:ProtInc. DR GO; GO:0007077; P:mitotic nuclear membrane disassembly; IMP:UniProtKB. DR GO; GO:0061744; P:motor behavior; IMP:ARUK-UCL. DR GO; GO:0007399; P:nervous system development; NAS:UniProtKB. DR GO; GO:0007528; P:neuromuscular junction development; IMP:ARUK-UCL. DR GO; GO:0050905; P:neuromuscular process; IMP:ARUK-UCL. DR GO; GO:0070050; P:neuron cellular homeostasis; IMP:ARUK-UCL. DR GO; GO:1990535; P:neuron projection maintenance; IMP:ARUK-UCL. DR GO; GO:1905515; P:non-motile cilium assembly; IMP:UniProtKB. DR GO; GO:0007097; P:nuclear migration; IBA:GO_Central. DR GO; GO:0090063; P:positive regulation of microtubule nucleation; IDA:UniProtKB. DR GO; GO:0031116; P:positive regulation of microtubule polymerization; IDA:UniProtKB. DR GO; GO:1904398; P:positive regulation of neuromuscular junction development; IMP:ARUK-UCL. DR GO; GO:0060236; P:regulation of mitotic spindle organization; IMP:UniProtKB. DR GO; GO:0042147; P:retrograde transport, endosome to Golgi; IMP:UniProtKB. DR GO; GO:0021517; P:ventral spinal cord development; IMP:ARUK-UCL. DR FunFam; 2.30.30.190:FF:000003; dynactin subunit 1 isoform X1; 1. DR Gene3D; 1.10.287.1490; -; 1. DR Gene3D; 2.30.30.190; CAP Gly-rich-like domain; 1. DR InterPro; IPR036859; CAP-Gly_dom_sf. DR InterPro; IPR000938; CAP-Gly_domain. DR InterPro; IPR022157; Dynactin. DR PANTHER; PTHR18916; DYNACTIN 1-RELATED MICROTUBULE-BINDING; 1. DR PANTHER; PTHR18916:SF6; DYNACTIN SUBUNIT 1; 1. DR Pfam; PF01302; CAP_GLY; 1. DR Pfam; PF12455; Dynactin; 1. DR SMART; SM01052; CAP_GLY; 1. DR SUPFAM; SSF74924; Cap-Gly domain; 1. DR PROSITE; PS00845; CAP_GLY_1; 1. DR PROSITE; PS50245; CAP_GLY_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Amyotrophic lateral sclerosis; KW Cell cycle; Cell division; Coiled coil; Cytoplasm; Cytoskeleton; Dynein; KW Microtubule; Mitosis; Neurodegeneration; Neuropathy; Nucleus; Parkinsonism; KW Phosphoprotein; Proteomics identification; Reference proteome; Transport; KW Ubl conjugation. FT CHAIN 1..1278 FT /note="Dynactin subunit 1" FT /id="PRO_0000083518" FT DOMAIN 48..90 FT /note="CAP-Gly" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00045" FT REGION 1..25 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 100..223 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 911..1278 FT /note="Interaction with HPS6" FT /evidence="ECO:0000269|PubMed:25189619" FT COILED 213..547 FT /evidence="ECO:0000255" FT COILED 943..1049 FT /evidence="ECO:0000255" FT COILED 1182..1211 FT /evidence="ECO:0000255" FT COMPBIAS 102..114 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 129..152 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 161..184 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 214..223 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 108 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 145 FT /note="Phosphothreonine; by SLK" FT /evidence="ECO:0000269|PubMed:23985322" FT MOD_RES 146 FT /note="Phosphothreonine; by SLK" FT /evidence="ECO:0000269|PubMed:23985322" FT MOD_RES 147 FT /note="Phosphothreonine; by SLK" FT /evidence="ECO:0000269|PubMed:23985322" FT MOD_RES 179 FT /note="Phosphoserine; by PLK1" FT /evidence="ECO:0000269|PubMed:20679239" FT MOD_RES 212 FT /note="Phosphoserine; by CDK1" FT /evidence="ECO:0000269|PubMed:20679239" FT VAR_SEQ 1..138 FT /note="MAQSKRHVYSRTPSGSRMSAEASARPLRVGSRVEVIGKGHRGTVAYVGATLF FT ATGKWVGVILDEAKGKNDGTVQGRKYFTCDEGHGIFVRQSQIQVFEDGADTTSPETPDS FT SASKVLKREGTDTTAKTSKLRGLKPKK -> MMRQ (in isoform p135 and FT isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_000760" FT VAR_SEQ 1..17 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_045392" FT VAR_SEQ 132..151 FT /note="Missing (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_045393" FT VAR_SEQ 132..138 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|PubMed:8856662" FT /id="VSP_047174" FT VAR_SEQ 1066..1070 FT /note="Missing (in isoform 3, isoform 4 and isoform 5)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_045394" FT VARIANT 52 FT /note="F -> L (in PERRYS; mutation carriers either do not FT develop depression or they do develop it late in the FT disease course; dbSNP:rs886039227)" FT /evidence="ECO:0000269|PubMed:24676999" FT /id="VAR_071452" FT VARIANT 59 FT /note="G -> S (in HMND14; reduced affinity for microtubules FT which has been suggested to impair axonal transport; the FT effect is identical to that of complete loss of the CAP-Gly FT domain; decreased interaction with MAPRE1; no effect on its FT interaction with TBCB; dbSNP:rs121909342)" FT /evidence="ECO:0000269|PubMed:12627231, FT ECO:0000269|PubMed:16505168, ECO:0000269|PubMed:19136952, FT ECO:0000269|PubMed:19279216, ECO:0000269|PubMed:22777741" FT /id="VAR_015850" FT VARIANT 71 FT /note="G -> A (in PERRYS; dbSNP:rs67586389)" FT /evidence="ECO:0000269|PubMed:19136952" FT /id="VAR_063867" FT VARIANT 71 FT /note="G -> E (in PERRYS; dbSNP:rs67586389)" FT /evidence="ECO:0000269|PubMed:19136952" FT /id="VAR_063868" FT VARIANT 71 FT /note="G -> R (in PERRYS; reduced microtubule binding; FT results in the accumulation of intracytoplasmic inclusions; FT loss of interaction with CLIP1; significant decrease in FT motility of dynein-dynactin complex along microtubules; FT dbSNP:rs72466485)" FT /evidence="ECO:0000269|PubMed:19136952, FT ECO:0000269|PubMed:24881494, ECO:0000269|PubMed:25185702, FT ECO:0000269|PubMed:26972003" FT /id="VAR_063869" FT VARIANT 72 FT /note="T -> P (in PERRYS; dbSNP:rs72466486)" FT /evidence="ECO:0000269|PubMed:19136952" FT /id="VAR_063870" FT VARIANT 74 FT /note="Q -> P (in PERRYS; diminishes microtubule binding FT and lead to intracytoplasmic inclusions; significant FT decrease in motility of dynein-dynactin complex along FT microtubules; defective in inhibiting microtubule FT catastrophe in neurons; dbSNP:rs72466487)" FT /evidence="ECO:0000269|PubMed:19136952, FT ECO:0000269|PubMed:23874158, ECO:0000269|PubMed:25185702" FT /id="VAR_063871" FT VARIANT 78 FT /note="Y -> C (in PERRYS; significantly reduced microtubule FT binding; dbSNP:rs886039229)" FT /evidence="ECO:0000269|PubMed:24881494" FT /id="VAR_071453" FT VARIANT 163 FT /note="A -> P" FT /id="VAR_001373" FT VARIANT 196 FT /note="I -> V (no effect of its interaction with TBCB; no FT loss of localization to microtubules; dbSNP:rs55862001)" FT /evidence="ECO:0000269|PubMed:17824900, FT ECO:0000269|PubMed:22777741" FT /id="VAR_076920" FT VARIANT 287 FT /note="L -> M (in dbSNP:rs13420401)" FT /id="VAR_048677" FT VARIANT 495 FT /note="R -> Q (in dbSNP:rs17721059)" FT /evidence="ECO:0000269|PubMed:17824900" FT /id="VAR_048678" FT VARIANT 571 FT /note="M -> T (in ALS; associated with disease FT susceptibility; dbSNP:rs121909343)" FT /evidence="ECO:0000269|PubMed:15326253" FT /id="VAR_063872" FT VARIANT 670 FT /note="Y -> F (found in a patient with hereditary motor and FT sensory neuropathy; uncertain significance; FT dbSNP:rs765819985)" FT /evidence="ECO:0000269|PubMed:24627108" FT /id="VAR_073287" FT VARIANT 785 FT /note="R -> W (in ALS; associated with disease FT susceptibility; dbSNP:rs121909344)" FT /evidence="ECO:0000269|PubMed:15326253" FT /id="VAR_063873" FT VARIANT 1101 FT /note="R -> K (in ALS; associated with disease FT susceptibility; dbSNP:rs121909345)" FT /evidence="ECO:0000269|PubMed:16240349" FT /id="VAR_063874" FT VARIANT 1249 FT /note="T -> I (in ALS; uncertain significance; FT dbSNP:rs72466496)" FT /evidence="ECO:0000269|PubMed:15326253, FT ECO:0000269|PubMed:17824900, ECO:0000269|PubMed:19506225" FT /id="VAR_063875" FT MUTAGEN 68 FT /note="K->A: Abolishes interaction with CLIP1." FT /evidence="ECO:0000269|PubMed:17828275" FT MUTAGEN 90 FT /note="R->E: Abolishes interaction with CLIP1." FT /evidence="ECO:0000269|PubMed:17828275" FT MUTAGEN 145 FT /note="T->A: Affects centrosomal localization; when FT associated with A-146 and A-147." FT /evidence="ECO:0000269|PubMed:23985322" FT MUTAGEN 146 FT /note="T->A: Affects centrosomal localization; when FT associated with A-145 and A-147." FT /evidence="ECO:0000269|PubMed:23985322" FT MUTAGEN 147 FT /note="T->A: Affects centrosomal localization; when FT associated with A-145 and A-146." FT /evidence="ECO:0000269|PubMed:23985322" FT MUTAGEN 179 FT /note="S->A: Non-phosphorylatable by PLK1. Decreased FT nuclear envelope localization. No loss of microtubule- FT binding. No effect on its interaction with CLIP1." FT /evidence="ECO:0000269|PubMed:20679239" FT MUTAGEN 179 FT /note="S->D: No loss of localization to nuclear envelope. FT Decrease in microtubule-binding. No effect on its FT interaction with CLIP1." FT /evidence="ECO:0000269|PubMed:20679239" FT MUTAGEN 212 FT /note="S->A: No effect on its interaction with CLIP1 and FT PLK1." FT /evidence="ECO:0000269|PubMed:20679239" FT CONFLICT 10 FT /note="S -> N (in Ref. 7; CAA67333)" FT /evidence="ECO:0000305" FT CONFLICT 257 FT /note="Q -> R (in Ref. 2; BAG59757)" FT /evidence="ECO:0000305" FT CONFLICT 349 FT /note="K -> R (in Ref. 2; AK314352)" FT /evidence="ECO:0000305" FT CONFLICT 368 FT /note="A -> V (in Ref. 2; AK314352)" FT /evidence="ECO:0000305" FT CONFLICT 526 FT /note="H -> N (in Ref. 5; AAH71583)" FT /evidence="ECO:0000305" FT CONFLICT 618 FT /note="K -> R (in Ref. 5; AAH71583)" FT /evidence="ECO:0000305" FT CONFLICT 712 FT /note="D -> V (in Ref. 7; CAA67333)" FT /evidence="ECO:0000305" FT CONFLICT 1081 FT /note="V -> M (in Ref. 9; AAP35404)" FT /evidence="ECO:0000305" FT CONFLICT 1261 FT /note="R -> Q (in Ref. 2; BAG59757)" FT /evidence="ECO:0000305" FT CONFLICT 1274 FT /note="S -> I (in Ref. 5; AAH71583)" FT /evidence="ECO:0000305" FT STRAND 17..19 FT /evidence="ECO:0007829|PDB:2COY" FT STRAND 32..35 FT /evidence="ECO:0007829|PDB:1TXQ" FT TURN 36..38 FT /evidence="ECO:0007829|PDB:1TXQ" FT STRAND 41..48 FT /evidence="ECO:0007829|PDB:1TXQ" FT STRAND 51..55 FT /evidence="ECO:0007829|PDB:1TXQ" FT STRAND 57..65 FT /evidence="ECO:0007829|PDB:1TXQ" FT STRAND 67..73 FT /evidence="ECO:0007829|PDB:1TXQ" FT STRAND 76..78 FT /evidence="ECO:0007829|PDB:1TXQ" FT TURN 83..85 FT /evidence="ECO:0007829|PDB:2HQH" FT STRAND 86..89 FT /evidence="ECO:0007829|PDB:1TXQ" FT HELIX 91..93 FT /evidence="ECO:0007829|PDB:1TXQ" FT STRAND 94..96 FT /evidence="ECO:0007829|PDB:1TXQ" SQ SEQUENCE 1278 AA; 141695 MW; 6DCEA5E67856E4BC CRC64; MAQSKRHVYS RTPSGSRMSA EASARPLRVG SRVEVIGKGH RGTVAYVGAT LFATGKWVGV ILDEAKGKND GTVQGRKYFT CDEGHGIFVR QSQIQVFEDG ADTTSPETPD SSASKVLKRE GTDTTAKTSK LRGLKPKKAP TARKTTTRRP KPTRPASTGV AGASSSLGPS GSASAGELSS SEPSTPAQTP LAAPIIPTPV LTSPGAVPPL PSPSKEEEGL RAQVRDLEEK LETLRLKRAE DKAKLKELEK HKIQLEQVQE WKSKMQEQQA DLQRRLKEAR KEAKEALEAK ERYMEEMADT ADAIEMATLD KEMAEERAES LQQEVEALKE RVDELTTDLE ILKAEIEEKG SDGAASSYQL KQLEEQNARL KDALVRMRDL SSSEKQEHVK LQKLMEKKNQ ELEVVRQQRE RLQEELSQAE STIDELKEQV DAALGAEEMV EMLTDRNLNL EEKVRELRET VGDLEAMNEM NDELQENARE TELELREQLD MAGARVREAQ KRVEAAQETV ADYQQTIKKY RQLTAHLQDV NRELTNQQEA SVERQQQPPP ETFDFKIKFA ETKAHAKAIE MELRQMEVAQ ANRHMSLLTA FMPDSFLRPG GDHDCVLVLL LMPRLICKAE LIRKQAQEKF ELSENCSERP GLRGAAGEQL SFAAGLVYSL SLLQATLHRY EHALSQCSVD VYKKVGSLYP EMSAHERSLD FLIELLHKDQ LDETVNVEPL TKAIKYYQHL YSIHLAEQPE DCTMQLADHI KFTQSALDCM SVEVGRLRAF LQGGQEATDI ALLLRDLETS CSDIRQFCKK IRRRMPGTDA PGIPAALAFG PQVSDTLLDC RKHLTWVVAV LQEVAAAAAQ LIAPLAENEG LLVAALEELA FKASEQIYGT PSSSPYECLR QSCNILISTM NKLATAMQEG EYDAERPPSK PPPVELRAAA LRAEITDAEG LGLKLEDRET VIKELKKSLK IKGEELSEAN VRLSLLEKKL DSAAKDADER IEKVQTRLEE TQALLRKKEK EFEETMDALQ ADIDQLEAEK AELKQRLNSQ SKRTIEGLRG PPPSGIATLV SGIAGEEQQR GAIPGQAPGS VPGPGLVKDS PLLLQQISAM RLHISQLQHE NSILKGAQMK ASLASLPPLH VAKLSHEGPG SELPAGALYR KTSQLLETLN QLSTHTHVVD ITRTSPAAKS PSAQLMEQVA QLKSLSDTVE KLKDEVLKET VSQRPGATVP TDFATFPSSA FLRAKEEQQD DTVYMGKVTF SCAAGFGQRH RLVLTQEQLH QLHSRLIS // ID DPOG1_HUMAN Reviewed; 1239 AA. AC P54098; Q8NFM2; Q92515; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 28-JAN-2026, entry version 236. DE RecName: Full=DNA polymerase subunit gamma-1; DE EC=2.7.7.7 {ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:19837034, ECO:0000269|PubMed:9558343}; DE AltName: Full=3'-5' exodeoxyribonuclease; DE EC=3.1.11.- {ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:26095671, ECO:0000269|PubMed:9558343}; DE AltName: Full=5'-deoxyribose-phosphate lyase; DE EC=4.2.99.- {ECO:0000269|PubMed:9770471}; DE AltName: Full=Mitochondrial DNA polymerase catalytic subunit; DE AltName: Full=PolG-alpha; GN Name=POLG {ECO:0000303|PubMed:10827171, ECO:0000312|HGNC:HGNC:9179}; GN Synonyms=MDP1, POLG1 {ECO:0000303|PubMed:12707443}, POLGA; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND DOMAIN. RX PubMed=8884268; DOI=10.1006/geno.1996.0490; RA Ropp P.A., Copeland W.C.; RT "Cloning and characterization of the human mitochondrial DNA polymerase, RT DNA polymerase gamma."; RL Genomics 36:449-458(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=9034326; DOI=10.1016/s0378-1119(96)00663-4; RA Lecrenier N.L., van der Bruggen P., Foury F.; RT "Mitochondrial DNA polymerases from yeast to man: a new family of RT polymerases."; RL Gene 185:147-152(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT GLN-GLN-55 INS. RC TISSUE=Brain; RA Watanabe T.K., Shimizu F., Nishino N., Fujiwara T., Kanemoto N., Suzuki M., RA Nakamura Y., Hirai Y., Maekawa H., Takahashi E.; RL Submitted (MAR-1996) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLN-55 INS; GLN-193; RP CYS-546; LYS-662; TRP-1142; GLY-1143; CYS-1146 AND HIS-1236. RG NIEHS SNPs program; RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lymph, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=9558343; DOI=10.1021/bi972685u; RA Graves S.W., Johnson A.A., Johnson K.A.; RT "Expression, purification, and initial kinetic characterization of the RT large subunit of the human mitochondrial DNA polymerase."; RL Biochemistry 37:6050-6058(1998). RN [7] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=9770471; DOI=10.1073/pnas.95.21.12244; RA Longley M.J., Prasad R., Srivastava D.K., Wilson S.H., Copeland W.C.; RT "Identification of 5'-deoxyribose phosphate lyase activity in human DNA RT polymerase gamma and its role in mitochondrial base excision repair in RT vitro."; RL Proc. Natl. Acad. Sci. U.S.A. 95:12244-12248(1998). RN [8] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP ASP-198; ASP-890 AND ASP-1135. RX PubMed=10827171; DOI=10.1074/jbc.m000559200; RA Spelbrink J.N., Toivonen J.M., Hakkaart G.A., Kurkela J.M., Cooper H.M., RA Lehtinen S.K., Lecrenier N., Back J.W., Speijer D., Foury F., Jacobs H.T.; RT "In vivo functional analysis of the human mitochondrial DNA polymerase POLG RT expressed in cultured human cells."; RL J. Biol. Chem. 275:24818-24828(2000). RN [9] RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND MUTAGENESIS OF GLU-200. RX PubMed=11477093; DOI=10.1074/jbc.m106045200; RA Johnson A.A., Johnson K.A.; RT "Fidelity of nucleotide incorporation by human mitochondrial DNA RT polymerase."; RL J. Biol. Chem. 276:38090-38096(2001). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT. RX PubMed=11477094; DOI=10.1074/jbc.m106046200; RA Johnson A.A., Johnson K.A.; RT "Exonuclease proofreading by human mitochondrial DNA polymerase."; RL J. Biol. Chem. 276:38097-38107(2001). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT. RX PubMed=11504725; DOI=10.1074/jbc.m105230200; RA Longley M.J., Nguyen D., Kunkel T.A., Copeland W.C.; RT "The fidelity of human DNA polymerase gamma with and without exonucleolytic RT proofreading and the p55 accessory subunit."; RL J. Biol. Chem. 276:38555-38562(2001). RN [12] RP REVIEW, AND DOMAIN. RX PubMed=15189144; DOI=10.1146/annurev.biochem.72.121801.161455; RA Kaguni L.S.; RT "DNA polymerase gamma, the mitochondrial replicase."; RL Annu. Rev. Biochem. 73:293-320(2004). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT. RX PubMed=15167897; DOI=10.1038/sj.emboj.7600257; RA Korhonen J.A., Pham X.H., Pellegrini M., Falkenberg M.; RT "Reconstitution of a minimal mtDNA replisome in vitro."; RL EMBO J. 23:2423-2429(2004). RN [14] RP SUBCELLULAR LOCATION, ASSOCIATION WITH MITOCHONDRIAL DNA, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=18063578; DOI=10.1074/jbc.m708444200; RA Bogenhagen D.F., Rousseau D., Burke S.; RT "The layered structure of human mitochondrial DNA nucleoids."; RL J. Biol. Chem. 283:3665-3675(2008). RN [15] RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-274, CHARACTERIZATION OF RP VARIANT LS HIS-232, CHARACTERIZATION OF VARIANTS PEOB1 ALA-268 AND ARG-304, RP AND CHARACTERIZATION OF VARIANTS GLN-275; LEU-277; ARG-303 AND ARG-305. RX PubMed=26095671; DOI=10.1038/ncomms8303; RA Macao B., Uhler J.P., Siibak T., Zhu X., Shi Y., Sheng W., Olsson M., RA Stewart J.B., Gustafsson C.M., Falkenberg M.; RT "The exonuclease activity of DNA polymerase gamma is required for ligation RT during mitochondrial DNA replication."; RL Nat. Commun. 6:7303-7303(2015). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [17] RP INTERACTION WITH TTC3. RX PubMed=29290964; DOI=10.18632/oncotarget.22476; RA Gong Y., Wang X., Shang X., Xiao S.P., Li W., Shang Y., Dou F.; RT "Tetratricopeptide repeat domain 3 overexpression tends to form aggregates RT and inhibit ubiquitination and degradation of DNA polymerase gamma."; RL Oncotarget 8:106475-106485(2017). RN [18] RP INTERACTION WITH LIG3. RX PubMed=33855352; DOI=10.1093/brain/awab056; RA Bonora E., Chakrabarty S., Kellaris G., Tsutsumi M., Bianco F., RA Bergamini C., Ullah F., Isidori F., Liparulo I., Diquigiovanni C., RA Masin L., Rizzardi N., Cratere M.G., Boschetti E., Papa V., Maresca A., RA Cenacchi G., Casadio R., Martelli P., Matera I., Ceccherini I., Fato R., RA Raiola G., Arrigo S., Signa S., Sementa A.R., Severino M., Striano P., RA Fiorillo C., Goto T., Uchino S., Oyazato Y., Nakamura H., Mishra S.K., RA Yeh Y.S., Kato T., Nozu K., Tanboon J., Morioka I., Nishino I., Toda T., RA Goto Y.I., Ohtake A., Kosaki K., Yamaguchi Y., Nonaka I., Iijima K., RA Mimaki M., Kurahashi H., Raams A., MacInnes A., Alders M., Engelen M., RA Linthorst G., de Koning T., den Dunnen W., Dijkstra G., van Spaendonck K., RA van Gent D.C., Aronica E.M., Picco P., Carelli V., Seri M., Katsanis N., RA Duijkers F.A.M., Taniguchi-Ikeda M., De Giorgio R.; RT "Biallelic variants in LIG3 cause a novel mitochondrial RT neurogastrointestinal encephalomyopathy."; RL Brain 144:1451-1466(2021). RN [19] RP X-RAY CRYSTALLOGRAPHY (3.24 ANGSTROMS) OF 70-1239, FUNCTION, CATALYTIC RP ACTIVITY, SUBUNIT, AND MUTAGENESIS OF 543-VAL--LEU-558; LEU-549; LEU-552 RP AND LYS-553. RX PubMed=19837034; DOI=10.1016/j.cell.2009.07.050; RA Lee Y.S., Kennedy W.D., Yin Y.W.; RT "Structural insight into processive human mitochondrial DNA synthesis and RT disease-related polymerase mutations."; RL Cell 139:312-324(2009). RN [20] RP X-RAY CRYSTALLOGRAPHY (3.30 ANGSTROMS) OF 30-1239 IN COMPLEX WITH MG(2+); RP PRIMER-TEMPLATE; 2',3'-DIDEOXYCYTIDINE 5'-TRIPHOSPHATE AND INHIBITOR RP ZALCITABINE, COFACTOR, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, RP SUBUNIT, MUTAGENESIS OF LYS-498; LYS-499 AND LYS-501, AND DOMAIN. RX PubMed=26056153; DOI=10.15252/embj.201591520; RA Szymanski M.R., Kuznetsov V.B., Shumate C., Meng Q., Lee Y.S., Patel G., RA Patel S., Yin Y.W.; RT "Structural basis for processivity and antiviral drug toxicity in human RT mitochondrial DNA replicase."; RL EMBO J. 34:1959-1970(2015). RN [21] RP STRUCTURE BY ELECTRON MICROSCOPY (2.46 ANGSTROMS) IN COMPLEX WITH RP 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, RP ACTIVE SITE, SITE, AND MUTAGENESIS OF ASP-198; GLU-200 AND ARG-853. RX PubMed=37202477; DOI=10.1038/s41594-023-00980-2; RA Park J., Herrmann G.K., Mitchell P.G., Sherman M.B., Yin Y.W.; RT "Polgamma coordinates DNA synthesis and proofreading to ensure RT mitochondrial genome integrity."; RL Nat. Struct. Mol. Biol. 30:812-823(2023). RN [22] RP VARIANTS PEOB1 PRO-3; ARG-304; THR-467 AND CYS-955. RX PubMed=11431686; DOI=10.1038/90034; RA Van Goethem G., Dermaut B., Loefgren A., Martin J.-J., Van Broeckhoven C.; RT "Mutation of POLG is associated with progressive external ophthalmoplegia RT characterized by mtDNA deletions."; RL Nat. Genet. 28:211-212(2001). RN [23] RP VARIANTS PEOA1 ASP-923; HIS-943; CYS-955; SER-957 AND LEU-1176, AND RP VARIANTS PEOB1 ILE-251; LEU-309 AND SER-848. RX PubMed=12210792; DOI=10.1002/ana.10278; RA Lamantea E., Tiranti V., Bordoni A., Toscano A., Bono F., Servidei S., RA Papadimitriou A., Spelbrink H., Silvestri L., Casari G., Comi G.P., RA Zeviani M.; RT "Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of RT autosomal dominant or recessive progressive external ophthalmoplegia."; RL Ann. Neurol. 52:211-219(2002). RN [24] RP CHARACTERIZATION OF VARIANT PEOA1 CYS-955, FUNCTION, AND CATALYTIC RP ACTIVITY. RX PubMed=11897778; DOI=10.1074/jbc.c200100200; RA Ponamarev M.V., Longley M.J., Nguyen D., Kunkel T.A., Copeland W.C.; RT "Active site mutation in DNA polymerase gamma associated with progressive RT external ophthalmoplegia causes error-prone DNA synthesis."; RL J. Biol. Chem. 277:15225-15228(2002). RN [25] RP VARIANTS PEOB1 TRP-579; LEU-587; THR-889 AND VAL-1076, AND VARIANT RP HIS-1236. RX PubMed=12975295; DOI=10.1001/archneur.60.9.1279; RA Filosto M., Mancuso M., Nishigaki Y., Pancrudo J., Harati Y., Gooch C., RA Mankodi A., Bayne L., Bonilla E., Shanske S., Hirano M., DiMauro S.; RT "Clinical and genetic heterogeneity in progressive external ophthalmoplegia RT due to mutations in polymerase gamma."; RL Arch. Neurol. 60:1279-1284(2003). RN [26] RP VARIANTS MTDPS4B ILE-251; LEU-587 AND SER-864. RX PubMed=12825077; DOI=10.1038/sj.ejhg.5201002; RA Van Goethem G., Schwartz M., Loefgren A., Dermaut B., Van Broeckhoven C., RA Vissing J.; RT "Novel POLG mutations in progressive external ophthalmoplegia mimicking RT mitochondrial neurogastrointestinal encephalomyopathy."; RL Eur. J. Hum. Genet. 11:547-549(2003). RN [27] RP VARIANT PEOB1 SER-848. RX PubMed=12872260; DOI=10.1002/humu.10246; RA Van Goethem G., Loefgren A., Dermaut B., Ceuterick C., Martin J.-J., RA Van Broeckhoven C.; RT "Digenic progressive external ophthalmoplegia in a sporadic patient: RT recessive mutations in POLG and C10orf2/Twinkle."; RL Hum. Mutat. 22:175-176(2003). RN [28] RP VARIANTS PEOB1 ILE-251; ALA-268; ARG-312; THR-467; GLN-562; LEU-587; RP PRO-807 AND TYR-932, AND VARIANTS GLY-1143 AND HIS-1236. RX PubMed=14635118; DOI=10.1002/humu.9203; RA Di Fonzo A., Bordoni A., Crimi M., Sara G., Del Bo R., Bresolin N., RA Comi G.P.; RT "POLG mutations in sporadic mitochondrial disorders with multiple mtDNA RT deletions."; RL Hum. Mutat. 22:498-499(2003). RN [29] RP VARIANTS PEOB1 TRP-227; ILE-251; ARG-312; VAL-431; THR-467; GLN-1047; RP CYS-1096 AND CYS-1104. RX PubMed=12707443; DOI=10.1212/01.wnl.0000056088.09408.3c; RA Agostino A., Valletta L., Chinnery P.F., Ferrari G., Carrara F., RA Taylor R.W., Schaefer A.M., Turnbull D.M., Tiranti V., Zeviani M.; RT "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external RT ophthalmoplegia (PEO)."; RL Neurology 60:1354-1356(2003). RN [30] RP VARIANT SCAE THR-467. RX PubMed=14694057; DOI=10.1212/01.wnl.0000098997.23471.65; RA Van Goethem G., Mercelis R., Loefgren A., Seneca S., Ceuterick C., RA Martin J.-J., Van Broeckhoven C.; RT "Patient homozygous for a recessive POLG mutation presents with features of RT MERRF."; RL Neurology 61:1811-1813(2003). RN [31] RP VARIANTS SANDO PRO-3; ARG-304; THR-467; TRP-627 AND CYS-955. RX PubMed=12565911; DOI=10.1016/s0960-8966(02)00216-x; RA Van Goethem G., Martin J.-J., Dermaut B., Loefgren A., Wibail A., RA Ververken D., Tack P., Dehaene I., Van Zandijcke M., Moonen M., RA Ceuterick C., De Jonghe P., Van Broeckhoven C.; RT "Recessive POLG mutations presenting with sensory and ataxic neuropathy in RT compound heterozygote patients with progressive external ophthalmoplegia."; RL Neuromuscul. Disord. 13:133-142(2003). RN [32] RP VARIANT MTDPS4A THR-467. RX PubMed=15122711; DOI=10.1002/ana.20079; RA Naviaux R.K., Nguyen K.V.; RT "POLG mutations associated with Alpers' syndrome and mitochondrial DNA RT depletion."; RL Ann. Neurol. 55:706-712(2004). RN [33] RP VARIANTS PEOB1 TRP-227; ILE-251; LEU-309; LEU-587; SER-848; ILE-1106 AND RP LEU-1176. RX PubMed=15349879; DOI=10.1002/ana.20219; RA Lamantea E., Zeviani M.; RT "Sequence analysis of familial PEO shows additional mutations associated RT with the 752C-->T and 3527C-->T changes in the POLG1 gene."; RL Ann. Neurol. 56:454-455(2004). RN [34] RP VARIANT PEOA1 CYS-831. RX PubMed=15534189; DOI=10.1001/archneur.61.11.1777; RA Mancuso M., Filosto M., Oh S.J., DiMauro S.; RT "A novel polymerase gamma mutation in a family with ophthalmoplegia, RT neuropathy, and parkinsonism."; RL Arch. Neurol. 61:1777-1779(2004). RN [35] RP VARIANTS PEOA1 CYS-953 AND CYS-955, AND VARIANTS PEOB1 ASP-468 AND RP THR-1105. RX PubMed=15351195; DOI=10.1016/s0140-6736(04)16983-3; RA Luoma P., Melberg A., Rinne J.O., Kaukonen J.A., Nupponen N.N., RA Chalmers R.M., Oldfors A., Rautakorpi I., Peltonen L., Majamaa K., RA Somer H., Suomalainen A.; RT "Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma RT mutations: clinical and molecular genetic study."; RL Lancet 364:875-882(2004). RN [36] RP VARIANTS SANDO TYR-932 AND ARG-1051. RX PubMed=14745080; DOI=10.1212/wnl.62.2.316; RA Mancuso M., Filosto M., Bellan M., Liguori R., Montagna P., Baruzzi A., RA DiMauro S., Carelli V.; RT "POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, RT ataxia, and deafness."; RL Neurology 62:316-318(2004). RN [37] RP VARIANT PEOB1 THR-467, VARIANT SANDO SER-748, AND VARIANT GLY-1143. RX PubMed=15477547; DOI=10.1212/01.wnl.0000140494.58732.83; RA Van Goethem G., Luoma P., Rantamaeki M., Al-Memar A., Kaakkola S., RA Hackman P., Krahe R., Loefgren A., Martin J.-J., De Jonghe P., RA Suomalainen A., Udd B., Van Broeckhoven C.; RT "POLG mutations in neurodegenerative disorders with ataxia but no muscle RT involvement."; RL Neurology 63:1251-1257(2004). RN [38] RP VARIANT SANDO SER-748, AND VARIANT GLY-1143. RX PubMed=16080118; DOI=10.1086/444548; RA Hakonen A.H., Heiskanen S., Juvonen V., Lappalainen I., Luoma P.T., RA Rantamaeki M., Van Goethem G., Loefgren A., Hackman P., Paetau A., RA Kaakkola S., Majamaa K., Varilo T., Udd B., Kaeaeriaeinen H., Bindoff L.A., RA Suomalainen A.; RT "Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal RT recessive ataxia with ancient European origin."; RL Am. J. Hum. Genet. 77:430-441(2005). RN [39] RP VARIANTS MTDPS4A SER-748 AND SER-848. RX PubMed=15929042; DOI=10.1002/ana.20498; RA Davidzon G., Mancuso M., Ferraris S., Quinzii C., Hirano M., Peters H.L., RA Kirby D., Thorburn D.R., DiMauro S.; RT "POLG mutations and Alpers syndrome."; RL Ann. Neurol. 57:921-923(2005). RN [40] RP VARIANTS MTDPS4A GLY-232; PRO-244; ILE-251; THR-467; LEU-587; SER-748; RP SER-848 AND PRO-957, AND VARIANT GLY-1143. RX PubMed=15689359; DOI=10.1093/brain/awh410; RA Ferrari G., Lamantea E., Donati A., Filosto M., Briem E., Carrara F., RA Parini R., Simonati A., Santer R., Zeviani M.; RT "Infantile hepatocerebral syndromes associated with mutations in the RT mitochondrial DNA polymerase-gammaA."; RL Brain 128:723-731(2005). RN [41] RP VARIANT PEOB1 THR-467, VARIANT SANDO GLN-627, VARIANT HIS-1236, RP CHARACTERIZATION OF VARIANT PEOB1 THR-467, CHARACTERIZATION OF VARIANT RP SANDO GLN-627, FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=15917273; DOI=10.1093/hmg/ddi196; RA Luoma P.T., Luo N., Loescher W.N., Farr C.L., Horvath R., Wanschitz J., RA Kiechl S., Kaguni L.S., Suomalainen A.; RT "Functional defects due to spacer-region mutations of human mitochondrial RT DNA polymerase in a family with an ataxia-myopathy syndrome."; RL Hum. Mol. Genet. 14:1907-1920(2005). RN [42] RP VARIANTS SANDO THR-467; HIS-497 AND SER-748. RX PubMed=15824347; DOI=10.1212/01.wnl.0000156516.77696.5a; RA Winterthun S., Ferrari G., He L., Taylor R.W., Zeviani M., Turnbull D.M., RA Engelsen B.A., Moen G., Bindoff L.A.; RT "Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial RT polymerase gamma mutations."; RL Neurology 64:1204-1208(2005). RN [43] RP VARIANTS PEOB1 ARG-737 AND TRP-853. RX PubMed=16634032; DOI=10.1002/ana.20831; RA Davidzon G., Greene P., Mancuso M., Klos K.J., Ahlskog J.E., Hirano M., RA DiMauro S.; RT "Early-onset familial parkinsonism due to POLG mutations."; RL Ann. Neurol. 59:859-862(2006). RN [44] RP VARIANTS PEOB1 LEU-603; TRP-853; CYS-1146 AND ASN-1184. RX PubMed=16401742; DOI=10.1001/archneur.63.1.107; RA Gonzalez-Vioque E., Blazquez A., Fernandez-Moreira D., Bornstein B., RA Bautista J., Arpa J., Navarro C., Campos Y., Fernandez-Moreno M.A., RA Garesse R., Arenas J., Martin M.A.; RT "Association of novel POLG mutations and multiple mitochondrial DNA RT deletions with variable clinical phenotypes in a Spanish population."; RL Arch. Neurol. 63:107-111(2006). RN [45] RP VARIANTS PEOB1 HIS-308; TRP-574 AND ARG-648, VARIANT SANDO VAL-517, AND RP VARIANTS MTDPS4A ASP-767; HIS-879; SER-885; PRO-914; HIS-1096 AND ASN-1191. RX PubMed=16621917; DOI=10.1093/brain/awl088; RA Horvath R., Hudson G., Ferrari G., Fuetterer N., Ahola S., Lamantea E., RA Prokisch H., Lochmueller H., McFarland R., Ramesh V., Klopstock T., RA Freisinger P., Salvi F., Mayr J.A., Santer R., Tesarova M., Zeman J., RA Udd B., Taylor R.W., Turnbull D., Hanna M., Fialho D., Suomalainen A., RA Zeviani M., Chinnery P.F.; RT "Phenotypic spectrum associated with mutations of the mitochondrial RT polymerase gamma gene."; RL Brain 129:1674-1684(2006). RN [46] RP VARIANTS PEOB1 ARG-304; ASP-380 AND THR-467, VARIANT SANDO SER-748, VARIANT RP MTDPS4A PRO-914, AND VARIANTS GLY-1143 AND HIS-1236. RX PubMed=16639411; DOI=10.1038/sj.ejhg.5201627; RA Naiemi M., Bannwarth S., Procaccio V., Pouget J., Desnuelle C., RA Pellissier J.-F., Roetig A., Munnich A., Calvas P., Richelme C., RA Jonveaux P., Castelnovo G., Simon M., Clanet M., Wallace D., RA Paquis-Flucklinger V.; RT "Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple RT deletions or depletion of mitochondrial DNA by a dHPLC-based assay."; RL Eur. J. Hum. Genet. 14:917-922(2006). RN [47] RP ERRATUM OF PUBMED:16639411. RA Naiemi M., Bannwarth S., Procaccio V., Pouget J., Desnuelle C., RA Pellissier J.-F., Roetig A., Munnich A., Calvas P., Richelme C., RA Jonveaux P., Castelnovo G., Simon M., Clanet M., Wallace D., RA Paquis-Flucklinger V.; RL Eur. J. Hum. Genet. 15:607-607(2006). RN [48] RP VARIANTS SANDO ARG-648 AND CYS-807. RX PubMed=16919951; DOI=10.1016/j.nmd.2006.05.016; RA Gago M.F., Rosas M.J., Guimaraes J., Ferreira M., Vilarinho L., Castro L., RA Carpenter S.; RT "SANDO: two novel mutations in POLG1 gene."; RL Neuromuscul. Disord. 16:507-509(2006). RN [49] RP VARIANT PEOA1 ASN-511, AND VARIANT PHE-463. RX PubMed=17420318; DOI=10.1001/archneur.64.4.553; RA Hudson G., Schaefer A.M., Taylor R.W., Tiangyou W., Gibson A., Venables G., RA Griffiths P., Burn D.J., Turnbull D.M., Chinnery P.F.; RT "Mutation of the linker region of the polymerase gamma-1 (POLG1) gene RT associated with progressive external ophthalmoplegia and Parkinsonism."; RL Arch. Neurol. 64:553-557(2007). RN [50] RP VARIANT PEOA1 CYS-831. RX PubMed=17846414; DOI=10.1212/01.wnl.0000276955.23735.eb; RA Luoma P.T., Eerola J., Ahola S., Hakonen A.H., Hellstroem O., RA Kivistoe K.T., Tienari P.J., Suomalainen A.; RT "Mitochondrial DNA polymerase gamma variants in idiopathic sporadic RT Parkinson disease."; RL Neurology 69:1152-1159(2007). RN [51] RP VARIANT PEOA1 HIS-1186. RX PubMed=18575922; DOI=10.1007/s00415-008-0926-3; RA Virgilio R., Ronchi D., Hadjigeorgiou G.M., Bordoni A., Saladino F., RA Moggio M., Adobbati L., Kafetsouli D., Tsironi E., Previtali S., RA Papadimitriou A., Bresolin N., Comi G.P.; RT "Novel Twinkle (PEO1) gene mutations in Mendelian progressive external RT ophthalmoplegia."; RL J. Neurol. 255:1384-1391(2008). RN [52] RP VARIANTS LS HIS-232 AND SER-848, VARIANTS MTDPS4A ILE-251; THR-467; RP LEU-587; SER-748; CYS-831; SER-848; PRO-914; TYR-1110; ARG-1134 AND RP LYS-1136, AND VARIANTS GLY-1143 AND HIS-1236. RX PubMed=18828154; DOI=10.1002/humu.20852; RA Taanman J.-W., Rahman S., Pagnamenta A.T., Morris A.A.M., RA Bitner-Glindzicz M., Wolf N.I., Leonard J.V., Clayton P.T., RA Schapira A.H.V.; RT "Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA RT depletion."; RL Hum. Mutat. 30:248-254(2009). RN [53] RP VARIANTS MTDPS4B TRP-227 AND SER-848. RX PubMed=19307547; DOI=10.1212/01.wnl.0000345002.47396.e1; RA Giordano C., Powell H., Leopizzi M., de Curtis M., Travaglini C., RA Sebastiani M., Gallo P., Taylor R.W., d'Amati G.; RT "Fatal congenital myopathy and gastrointestinal pseudo-obstruction due to RT POLG1 mutations."; RL Neurology 72:1103-1105(2009). RN [54] RP VARIANTS SCAE THR-467 AND SER-748, AND VARIANTS MTDPS4A ARG-303; THR-467 RP AND SER-848. RX PubMed=20400524; DOI=10.1093/brain/awq067; RA Tzoulis C., Neckelmann G., Moerk S.J., Engelsen B.E., Viscomi C., Moen G., RA Ersland L., Zeviani M., Bindoff L.A.; RT "Localized cerebral energy failure in DNA polymerase gamma-associated RT encephalopathy syndromes."; RL Brain 133:1428-1437(2010). RN [55] RP VARIANTS PEOB1 LEU-277 AND CYS-943. RX PubMed=21301859; DOI=10.1007/s00415-011-5936-x; RA Sato K., Yabe I., Yaguchi H., Nakano F., Kunieda Y., Saitoh S., Sasaki H.; RT "Genetic analysis of two Japanese families with progressive external RT ophthalmoplegia and parkinsonism."; RL J. Neurol. 258:1327-1332(2011). RN [56] RP VARIANTS MTDPS4A ARG-305; THR-467; SER-748; SER-848; CYS-852 AND ARG-966. RX PubMed=22000311; DOI=10.1016/j.pediatrneurol.2011.07.008; RA Hunter M.F., Peters H., Salemi R., Thorburn D., Mackay M.T.; RT "Alpers syndrome with mutations in POLG: clinical and investigative RT features."; RL Pediatr. Neurol. 45:311-318(2011). RN [57] RP VARIANT MTDPS4A CYS-1096. RX PubMed=25129007; DOI=10.1007/s13312-014-0475-z; RA Bijarnia-Mahay S., Mohan N., Goyal D., Verma I.C.; RT "Mitochondrial DNA depletion syndrome causing liver failure."; RL Indian Pediatr. 51:666-668(2014). RN [58] RP INVOLVEMENT IN SCAE, AND VARIANTS SCAE THR-467; HIS-497 AND SER-748. RX PubMed=26942291; DOI=10.1016/j.ajhg.2016.01.009; RA Sandford E., Bird T.D., Li J.Z., Burmeister M.; RT "PRICKLE2 mutations might not be involved in epilepsy."; RL Am. J. Hum. Genet. 98:588-589(2016). RN [59] RP VARIANTS GLN-275 AND SER-848. RX PubMed=30552426; DOI=10.1038/s41431-018-0299-8; RA Papuc S.M., Abela L., Steindl K., Begemann A., Simmons T.L., Schmitt B., RA Zweier M., Oneda B., Socher E., Crowther L.M., Wohlrab G., Gogoll L., RA Poms M., Seiler M., Papik M., Baldinger R., Baumer A., Asadollahi R., RA Kroell-Seger J., Schmid R., Iff T., Schmitt-Mechelke T., Otten K., RA Hackenberg A., Addor M.C., Klein A., Azzarello-Burri S., Sticht H., RA Joset P., Plecko B., Rauch A.; RT "The role of recessive inheritance in early-onset epileptic RT encephalopathies: a combined whole-exome sequencing and copy number RT study."; RL Eur. J. Hum. Genet. 27:408-421(2019). CC -!- FUNCTION: Catalytic subunit of DNA polymerase gamma solely responsible CC for replication of mitochondrial DNA (mtDNA). Replicates both heavy and CC light strands of the circular mtDNA genome using a single-stranded DNA CC template, RNA primers and the four deoxyribonucleoside triphosphates as CC substrates (PubMed:11477093, PubMed:11897778, PubMed:15917273, CC PubMed:19837034, PubMed:9558343). Has 5' -> 3' polymerase activity. CC Functionally interacts with TWNK and SSBP1 at the replication fork to CC form a highly processive replisome, where TWNK unwinds the double- CC stranded DNA template prior to replication and SSBP1 covers the CC parental heavy strand to enable continuous replication of the entire CC mitochondrial genome. A single nucleotide incorporation cycle includes CC binding of the incoming nucleotide at the insertion site, a CC phosphodiester bond formation reaction that extends the 3'-end of the CC primer DNA, and translocation of the primer terminus to the post- CC insertion site. After completing replication of a mtDNA strand, CC mediates 3' -> 5' exonucleolytic degradation at the nick to enable CC proper ligation (PubMed:11477093, PubMed:11897778, PubMed:15167897, CC PubMed:15917273, PubMed:19837034, PubMed:26095671, PubMed:9558343). CC Highly accurate due to high nucleotide selectivity and 3' -> 5' CC exonucleolytic proofreading. Proficiently corrects base substitutions, CC single-base additions and deletions in non-repetitive sequences and CC short repeats, but displays lower proofreading activity when CC replicating longer homopolymeric stretches. Exerts exonuclease activity CC toward single-stranded DNA and double-stranded DNA containing 3'- CC terminal mispairs. When a misincorporation occurs, transitions from CC replication to a pro-nucleolytic editing mode and removes the CC missincorporated nucleoside in the exonuclease active site. Proceeds CC via an SN2 nucleolytic mechanism in which Asp-198 catalyzes CC phosphodiester bond hydrolysis and Glu-200 stabilizes the leaving CC group. As a result the primer strand becomes one nucleotide shorter and CC is positioned in the post-insertion site, ready to resume DNA synthesis CC (PubMed:10827171, PubMed:11477094, PubMed:11504725, PubMed:37202477). CC Exerts 5'-deoxyribose phosphate (dRP) lyase activity and mediates CC repair-associated mtDNA synthesis (gap filling) in base-excision repair CC pathway. Catalyzes the release of the 5'-terminal 2-deoxyribose-5- CC phosphate sugar moiety from incised apurinic/apyrimidinic (AP) sites to CC produce a substrate for DNA ligase. The dRP lyase reaction does not CC require divalent metal ions and likely proceeds via a Schiff base CC intermediate in a beta-elimination reaction mechanism (PubMed:9770471). CC {ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11504725, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26095671, ECO:0000269|PubMed:37202477, CC ECO:0000269|PubMed:9558343, ECO:0000269|PubMed:9770471}. CC -!- CATALYTIC ACTIVITY: CC Reaction=DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + CC diphosphate; Xref=Rhea:RHEA:22508, Rhea:RHEA-COMP:17339, Rhea:RHEA- CC COMP:17340, ChEBI:CHEBI:33019, ChEBI:CHEBI:61560, ChEBI:CHEBI:173112; CC EC=2.7.7.7; Evidence={ECO:0000269|PubMed:10827171, CC ECO:0000269|PubMed:11477093, ECO:0000269|PubMed:11897778, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:15917273, CC ECO:0000269|PubMed:19837034, ECO:0000269|PubMed:26056153, CC ECO:0000269|PubMed:26095671, ECO:0000269|PubMed:37202477, CC ECO:0000269|PubMed:9558343}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22509; CC Evidence={ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26056153, ECO:0000269|PubMed:26095671, CC ECO:0000269|PubMed:37202477, ECO:0000269|PubMed:9558343}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 3'-end 2'-deoxyribonucleotidyl-deoxyribonucleotide-DNA + H2O CC = a 3'-end 2'-deoxyribonucleotide-DNA + a 2'-deoxyribonucleoside 5'- CC phosphate + H(+); Xref=Rhea:RHEA:77911, Rhea:RHEA-COMP:13863, CC Rhea:RHEA-COMP:19009, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:65317, ChEBI:CHEBI:138148, ChEBI:CHEBI:228185; CC Evidence={ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477094, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:26095671, CC ECO:0000269|PubMed:9558343}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:77912; CC Evidence={ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477094, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:26095671, CC ECO:0000269|PubMed:9558343}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 5'-end 2'-deoxyribose-2'-deoxyribonucleotide-DNA = (2E,4S)- CC 4-hydroxypenten-2-al-5-phosphate + a 5'-end 5'-phospho-2'- CC deoxyribonucleoside-DNA + H(+); Xref=Rhea:RHEA:76255, Rhea:RHEA- CC COMP:13180, Rhea:RHEA-COMP:18657, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:136412, ChEBI:CHEBI:195194, ChEBI:CHEBI:195195; CC Evidence={ECO:0000269|PubMed:9770471}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76256; CC Evidence={ECO:0000269|PubMed:9770471}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:26056153}; CC -!- ACTIVITY REGULATION: Inhibited by dideoxynucleotides such as antiviral CC agent zalcitabine. {ECO:0000269|PubMed:26056153}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.011 uM for dTTP (POLG polymerase activity at matched G:C primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=0.015 uM for dTTP (POLG:POLG2 polymerase activity at matched G:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=5.5 uM for dTTP (POLG polymerase activity at mismatched A:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=7.6 uM for dTTP (POLG:POLG2 polymerase activity at mismatched A:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=10 uM for dTTP (POLG polymerase activity at mismatched T:C primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=5.5 uM for dTTP (POLG:POLG2 polymerase activity at mismatched T:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=13 uM for dTTP (POLG polymerase activity at mismatched G:G primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=11 uM for dTTP (POLG:POLG2 polymerase activity at mismatched G:G CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=55 uM for dTTP (POLG polymerase activity at mismatched C:C primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=11 uM for dTTP (POLG:POLG2 polymerase activity at mismatched C:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC -!- SUBUNIT: Heterotrimer composed of a catalytic subunit and a homodimer CC of accessory subunits (POLG:POLG2) (PubMed:11477093, PubMed:11477094, CC PubMed:15167897, PubMed:19837034, PubMed:26056153, PubMed:37202477). CC Interacts with TTC3 (PubMed:29290964). Interacts with LIG3 CC (PubMed:33855352). {ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:19837034, ECO:0000269|PubMed:26056153, CC ECO:0000269|PubMed:37202477}. CC -!- INTERACTION: CC P54098; Q9UHN1: POLG2; NbExp=15; IntAct=EBI-852624, EBI-852642; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:10827171, CC ECO:0000269|PubMed:18063578}. Mitochondrion matrix, mitochondrion CC nucleoid {ECO:0000269|PubMed:18063578}. CC -!- DOMAIN: The polymerase domain encompasses three conserved active site CC motifs: Pol A (residues 887-896), Pol B (residues 943-958) and Pol C CC (residues 1134-1141). Binds the incoming dNTPs and undergoes an open to CC close coformation change to catalyze the formation of phosphodiester CC bond. {ECO:0000269|PubMed:26056153, ECO:0000303|PubMed:15189144, CC ECO:0000303|PubMed:8884268}. CC -!- DOMAIN: The 3' -> 5' exonuclease domain comprises three conserved CC active site motifs: Exo I (residues 196-200), Exo II (residues 267-275) CC and Exo III (residues 395-403). Proofreads the newly synthesized DNA CC strand. {ECO:0000269|PubMed:37202477, ECO:0000303|PubMed:15189144, CC ECO:0000303|PubMed:8884268}. CC -!- DOMAIN: The trigger loop contracts to enable correctly matched primer- CC template pair entry into the polymerase domain and extends to preclude CC the mismatched one. {ECO:0000269|PubMed:37202477}. CC -!- DOMAIN: The accessory determinant domain (AID) interacts with POLG2 CC proximal monomer. {ECO:0000269|PubMed:26056153}. CC -!- POLYMORPHISM: The poly-Gln region seems to be polymorphic. CC {ECO:0000269|Ref.3, ECO:0000269|Ref.4}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 1 (PEOA1) [MIM:157640]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:11897778, CC ECO:0000269|PubMed:12210792, ECO:0000269|PubMed:15351195, CC ECO:0000269|PubMed:15534189, ECO:0000269|PubMed:17420318, CC ECO:0000269|PubMed:17846414, ECO:0000269|PubMed:18575922}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal recessive, 1 (PEOB1) [MIM:258450]: A severe form CC of progressive external ophthalmoplegia, a disorder characterized by CC progressive weakness of ocular muscles and levator muscle of the upper CC eyelid. It is clinically more heterogeneous than the autosomal dominant CC forms. {ECO:0000269|PubMed:11431686, ECO:0000269|PubMed:12210792, CC ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:12872260, CC ECO:0000269|PubMed:12975295, ECO:0000269|PubMed:14635118, CC ECO:0000269|PubMed:15349879, ECO:0000269|PubMed:15351195, CC ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15917273, CC ECO:0000269|PubMed:16401742, ECO:0000269|PubMed:16621917, CC ECO:0000269|PubMed:16634032, ECO:0000269|PubMed:16639411, CC ECO:0000269|PubMed:21301859, ECO:0000269|PubMed:26095671}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Sensory ataxic neuropathy dysarthria and ophthalmoparesis CC (SANDO) [MIM:607459]: A systemic disorder resulting from mitochondrial CC dysfunction associated with mitochondrial depletion in skeletal muscle CC and peripheral nerve tissue. The clinical triad of symptoms consists of CC sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. However, CC the phenotype varies widely, even within the same family, and can also CC include myopathy, seizures, and hearing loss. CC {ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:14745080, CC ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15824347, CC ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:16080118, CC ECO:0000269|PubMed:16621917, ECO:0000269|PubMed:16639411, CC ECO:0000269|PubMed:16919951}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 4A (MTDPS4A) CC [MIM:203700]: An autosomal recessive hepatocerebral syndrome due to CC mitochondrial dysfunction. The typical course of the disease includes CC severe developmental delay, intractable seizures, liver failure, and CC death in childhood. Refractory seizures, cortical blindness, CC progressive liver dysfunction, and acute liver failure after exposure CC to valproic acid are considered diagnostic features. The CC neuropathological hallmarks are neuronal loss, spongiform degeneration, CC and astrocytosis of the visual cortex. Liver biopsy results show CC steatosis, often progressing to cirrhosis. CC {ECO:0000269|PubMed:15122711, ECO:0000269|PubMed:15689359, CC ECO:0000269|PubMed:15929042, ECO:0000269|PubMed:16621917, CC ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18828154, CC ECO:0000269|PubMed:20400524, ECO:0000269|PubMed:22000311, CC ECO:0000269|PubMed:25129007}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 4B (MTDPS4B) CC [MIM:613662]: An autosomal recessive progressive multisystem disorder CC due to mitochondrial dysfunction. It is clinically characterized by CC chronic gastrointestinal dysmotility and pseudo-obstruction, cachexia, CC progressive external ophthalmoplegia, axonal sensory ataxic neuropathy, CC and muscle weakness. {ECO:0000269|PubMed:12825077, CC ECO:0000269|PubMed:19307547}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive CC neurodegenerative disorder characterized by the presence of focal, CC bilateral lesions in one or more areas of the central nervous system CC including the brainstem, thalamus, basal ganglia, cerebellum and spinal CC cord. Clinical features depend on which areas of the central nervous CC system are involved and include subacute onset of psychomotor CC retardation, hypotonia, ataxia, weakness, vision loss, eye movement CC abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:18828154, CC ECO:0000269|PubMed:26095671}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Spinocerebellar ataxia with epilepsy (SCAE) [MIM:607459]: An CC autosomal recessive syndrome characterized by headaches and/or seizures CC manifesting in childhood or adolescence, cerebellar and sensory ataxia, CC dysarthria, and myoclonus manifesting in early adulthood. CC Neuropathological findings include spinocerebellar degeneration CC associated with cortical neuronal degeneration in advanced cases. CC {ECO:0000269|PubMed:14694057, ECO:0000269|PubMed:20400524, CC ECO:0000269|PubMed:26942291}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the DNA polymerase type-A family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U60325; AAC50712.1; -; mRNA. DR EMBL; X98093; CAA66719.1; -; mRNA. DR EMBL; D84103; BAA12223.1; -; mRNA. DR EMBL; AF497906; AAM77583.1; -; Genomic_DNA. DR EMBL; BC042571; AAH42571.1; -; mRNA. DR EMBL; BC050559; AAH50559.1; -; mRNA. DR CCDS; CCDS10350.1; -. DR PIR; G02750; G02750. DR RefSeq; NP_001119603.1; NM_001126131.2. DR RefSeq; NP_002684.1; NM_002693.3. DR PDB; 3IKM; X-ray; 3.24 A; A/D=70-1239. DR PDB; 4ZTU; X-ray; 3.30 A; A=30-1239. DR PDB; 4ZTZ; X-ray; 3.44 A; A=30-1239. DR PDB; 5C51; X-ray; 3.43 A; A=25-1239. DR PDB; 5C52; X-ray; 3.64 A; A=25-1239. DR PDB; 5C53; X-ray; 3.57 A; A=25-1239. DR PDB; 8D33; EM; 2.46 A; A=1-1239. DR PDB; 8D37; EM; 2.65 A; A=1-1239. DR PDB; 8D3R; EM; 3.04 A; A=1-1239. DR PDB; 8D42; EM; 2.91 A; A=1-1239. DR PDB; 8G5I; EM; 2.75 A; A=1-1239. DR PDB; 8G5J; EM; 2.63 A; A=1-1239. DR PDB; 8G5K; EM; 2.90 A; A=1-1239. DR PDB; 8G5L; EM; 3.00 A; A=1-1239. DR PDB; 8G5M; EM; 2.58 A; A=1-1239. DR PDB; 8G5N; EM; 2.73 A; A=1-1239. DR PDB; 8G5O; EM; 2.61 A; A=1-1239. DR PDB; 8G5P; EM; 2.78 A; A=1-1239. DR PDB; 8T7E; EM; 3.08 A; A=1-1239. DR PDB; 8UDK; X-ray; 3.43 A; A=1-1239. DR PDB; 8UDL; EM; 2.37 A; A=1-1239. DR PDB; 8V54; EM; 4.10 A; A=26-1239. DR PDB; 8V55; EM; 4.20 A; A=26-1239. DR PDB; 8V5D; EM; 3.00 A; A=26-1239. DR PDB; 8V5R; EM; 3.00 A; A=26-1239. DR PDB; 9GGB; EM; 2.63 A; A=26-1239. DR PDB; 9GGC; EM; 2.39 A; A=26-1239. DR PDB; 9GGD; EM; 2.67 A; A=26-1239. DR PDB; 9GGE; EM; 2.69 A; A=26-1239. DR PDB; 9GGF; EM; 2.65 A; A=26-1239. DR PDB; 9IC1; EM; 2.73 A; A=26-1239. DR PDB; 9IC3; EM; 2.96 A; A=26-1239. DR PDBsum; 3IKM; -. DR PDBsum; 4ZTU; -. DR PDBsum; 4ZTZ; -. DR PDBsum; 5C51; -. DR PDBsum; 5C52; -. DR PDBsum; 5C53; -. DR PDBsum; 8D33; -. DR PDBsum; 8D37; -. DR PDBsum; 8D3R; -. DR PDBsum; 8D42; -. DR PDBsum; 8G5I; -. DR PDBsum; 8G5J; -. DR PDBsum; 8G5K; -. DR PDBsum; 8G5L; -. DR PDBsum; 8G5M; -. DR PDBsum; 8G5N; -. DR PDBsum; 8G5O; -. DR PDBsum; 8G5P; -. DR PDBsum; 8T7E; -. DR PDBsum; 8UDK; -. DR PDBsum; 8UDL; -. DR PDBsum; 8V54; -. DR PDBsum; 8V55; -. DR PDBsum; 8V5D; -. DR PDBsum; 8V5R; -. DR PDBsum; 9GGB; -. DR PDBsum; 9GGC; -. DR PDBsum; 9GGD; -. DR PDBsum; 9GGE; -. DR PDBsum; 9GGF; -. DR PDBsum; 9IC1; -. DR PDBsum; 9IC3; -. DR AlphaFoldDB; P54098; -. DR EMDB; EMD-27154; -. DR EMDB; EMD-27155; -. DR EMDB; EMD-27163; -. DR EMDB; EMD-27172; -. DR EMDB; EMD-29745; -. DR EMDB; EMD-29746; -. DR EMDB; EMD-29747; -. DR EMDB; EMD-29748; -. DR EMDB; EMD-29749; -. DR EMDB; EMD-29750; -. DR EMDB; EMD-29751; -. DR EMDB; EMD-29752; -. DR EMDB; EMD-41091; -. DR EMDB; EMD-42150; -. DR EMDB; EMD-42842; -. DR EMDB; EMD-42979; -. DR EMDB; EMD-42980; -. DR EMDB; EMD-42982; -. DR EMDB; EMD-42984; -. DR EMDB; EMD-51326; -. DR EMDB; EMD-51327; -. DR EMDB; EMD-51328; -. DR EMDB; EMD-51329; -. DR EMDB; EMD-51330; -. DR EMDB; EMD-52824; -. DR EMDB; EMD-52828; -. DR SMR; P54098; -. DR BioGRID; 111424; 116. DR ComplexPortal; CPX-2093; Mitochondrial DNA polymerase gamma complex. DR FunCoup; P54098; 1006. DR IntAct; P54098; 64. DR MINT; P54098; -. DR STRING; 9606.ENSP00000399851; -. DR BindingDB; P54098; -. DR ChEMBL; CHEMBL2732; -. DR DrugBank; DB12151; Brincidofovir. DR DrugCentral; P54098; -. DR GlyGen; P54098; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P54098; -. DR PhosphoSitePlus; P54098; -. DR SwissPalm; P54098; -. DR BioMuta; POLG; -. DR DMDM; 1706507; -. DR jPOST; P54098; -. DR MassIVE; P54098; -. DR PaxDb; 9606-ENSP00000268124; -. DR PeptideAtlas; P54098; -. DR ProteomicsDB; 56642; -. DR Pumba; P54098; -. DR Antibodypedia; 28558; 222 antibodies from 35 providers. DR DNASU; 5428; -. DR Ensembl; ENST00000268124.11; ENSP00000268124.5; ENSG00000140521.18. DR Ensembl; ENST00000442287.6; ENSP00000399851.2; ENSG00000140521.18. DR Ensembl; ENST00000636937.2; ENSP00000516154.1; ENSG00000140521.18. DR GeneID; 5428; -. DR KEGG; hsa:5428; -. DR MANE-Select; ENST00000268124.11; ENSP00000268124.5; NM_002693.3; NP_002684.1. DR UCSC; uc002bnr.5; human. DR AGR; HGNC:9179; -. DR ClinPGx; PA33500; -. DR CTD; 5428; -. DR DisGeNET; 5428; -. DR GeneCards; POLG; -. DR GeneReviews; POLG; -. DR HGNC; HGNC:9179; POLG. DR HPA; ENSG00000140521; Low tissue specificity. DR MalaCards; POLG; -. DR MIM; 157640; phenotype. DR MIM; 174763; gene. DR MIM; 203700; phenotype. DR MIM; 256000; phenotype. DR MIM; 258450; phenotype. DR MIM; 607459; phenotype. DR MIM; 613662; phenotype. DR OpenTargets; ENSG00000140521; -. DR Orphanet; 726; Alpers-Huttenlocher syndrome. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 254886; Autosomal recessive progressive external ophthalmoplegia. DR Orphanet; 298; Mitochondrial neurogastrointestinal encephalomyopathy. DR Orphanet; 402082; Progressive myoclonic epilepsy type 5. DR Orphanet; 94125; Recessive mitochondrial ataxia syndrome. DR Orphanet; 70595; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome. DR Orphanet; 254881; Spinocerebellar ataxia with epilepsy. DR VEuPathDB; HostDB:ENSG00000140521; -. DR eggNOG; KOG3657; Eukaryota. DR GeneTree; ENSGT00390000000453; -. DR HOGENOM; CLU_001524_2_2_1; -. DR InParanoid; P54098; -. DR OMA; AMHITNL; -. DR OrthoDB; 5588663at2759; -. DR PAN-GO; P54098; 4 GO annotations based on evolutionary models. DR PhylomeDB; P54098; -. DR PathwayCommons; P54098; -. DR Reactome; R-HSA-9913635; Strand-asynchronous mitochondrial DNA replication. DR SignaLink; P54098; -. DR SIGNOR; P54098; -. DR Agora; ENSG00000140521; -. DR BioGRID-ORCS; 5428; 224 hits in 1160 CRISPR screens. DR ChiTaRS; POLG; human. DR GeneWiki; POLG; -. DR GenomeRNAi; 5428; -. DR Pharos; P54098; Tchem. DR PRO; PR:P54098; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; P54098; protein. DR Bgee; ENSG00000140521; Expressed in granulocyte and 212 other cell types or tissues. DR ExpressionAtlas; P54098; baseline and differential. DR GO; GO:0005760; C:gamma DNA polymerase complex; IDA:UniProtKB. DR GO; GO:0000262; C:mitochondrial chromosome; IDA:FlyBase. DR GO; GO:0005759; C:mitochondrial matrix; IDA:ComplexPortal. DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:BHF-UCL. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0032991; C:protein-containing complex; IDA:MGI. DR GO; GO:0008408; F:3'-5' exonuclease activity; IDA:FlyBase. DR GO; GO:0051575; F:5'-deoxyribose-5-phosphate lyase activity; IDA:UniProtKB. DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB. DR GO; GO:0003887; F:DNA-directed DNA polymerase activity; IDA:UniProtKB. DR GO; GO:0002020; F:protease binding; IPI:UniProtKB. DR GO; GO:0008310; F:single-stranded DNA 3'-5' DNA exonuclease activity; IDA:UniProtKB. DR GO; GO:0006284; P:base-excision repair; IDA:UniProtKB. DR GO; GO:0006287; P:base-excision repair, gap-filling; IDA:MGI. DR GO; GO:0006259; P:DNA metabolic process; TAS:ProtInc. DR GO; GO:0045004; P:DNA replication proofreading; IDA:UniProtKB. DR GO; GO:0006261; P:DNA-templated DNA replication; IDA:UniProtKB. DR GO; GO:0006264; P:mitochondrial DNA replication; IDA:FlyBase. DR CDD; cd08641; DNA_pol_gammaA; 1. DR FunFam; 1.10.150.20:FF:000024; DNA polymerase gamma, catalytic subunit; 1. DR FunFam; 1.20.5.3960:FF:000002; DNA polymerase gamma, catalytic subunit; 1. DR FunFam; 3.30.420.390:FF:000001; DNA polymerase gamma, catalytic subunit; 1. DR FunFam; 3.30.420.390:FF:000002; DNA polymerase gamma, catalytic subunit; 1. DR Gene3D; 1.20.5.3960; -; 1. DR Gene3D; 3.30.420.390; -; 2. DR Gene3D; 3.30.70.370; -; 1. DR Gene3D; 1.10.150.20; 5' to 3' exonuclease, C-terminal subdomain; 1. DR InterPro; IPR019760; DNA-dir_DNA_pol_A_CS. DR InterPro; IPR002297; DNA-dir_DNA_pol_A_mt. DR InterPro; IPR001098; DNA-dir_DNA_pol_A_palm_dom. DR InterPro; IPR043502; DNA/RNA_pol_sf. DR InterPro; IPR041336; DNApol_Exo. DR InterPro; IPR047580; POLG_palm_dom. DR InterPro; IPR012337; RNaseH-like_sf. DR PANTHER; PTHR10267; DNA POLYMERASE SUBUNIT GAMMA-1; 1. DR PANTHER; PTHR10267:SF0; DNA POLYMERASE SUBUNIT GAMMA-1; 1. DR Pfam; PF18136; DNApol_Exo; 1. DR PIRSF; PIRSF000797; DNA_pol_mt; 1. DR PRINTS; PR00867; DNAPOLG. DR SMART; SM00482; POLAc; 1. DR SUPFAM; SSF56672; DNA/RNA polymerases; 1. DR SUPFAM; SSF53098; Ribonuclease H-like; 1. DR PROSITE; PS00447; DNA_POLYMERASE_A; 1. PE 1: Evidence at protein level; KW 3D-structure; Disease variant; DNA replication; DNA-binding; KW DNA-directed DNA polymerase; Epilepsy; Hydrolase; Leigh syndrome; Lyase; KW Magnesium; Mitochondrion; Mitochondrion nucleoid; Neurodegeneration; KW Neuropathy; Nucleotidyltransferase; Primary mitochondrial disease; KW Progressive external ophthalmoplegia; Proteomics identification; KW Reference proteome; Transferase. FT CHAIN 1..1239 FT /note="DNA polymerase subunit gamma-1" FT /id="PRO_0000101270" FT REGION 1..68 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 43..55 FT /note="Does not contribute to polymerase and exonuclease FT enzymatic activities" FT /evidence="ECO:0000269|PubMed:10827171" FT REGION 318..340 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 506..531 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 510..571 FT /note="Accessory-interacting determinant" FT /evidence="ECO:0000269|PubMed:26056153" FT REGION 858..864 FT /note="Trigger loop" FT /evidence="ECO:0000269|PubMed:37202477" FT MOTIF 196..200 FT /note="Exo I" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 267..275 FT /note="Exo II" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 395..403 FT /note="Exo III" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 887..896 FT /note="Pol A" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 943..958 FT /note="Pol B" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 1134..1141 FT /note="Pol C" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT COMPBIAS 9..36 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 44..60 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 198 FT /note="Exonuclease activity" FT /evidence="ECO:0000269|PubMed:37202477" FT BINDING 306 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 579 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 593 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 754 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 763 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 768 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 806 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 849 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 863 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 869 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 890 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 890 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 890 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 891 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 891 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 893 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 895 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 943 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 947 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 951 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 1094 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 1095 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 1135 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 1135 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 1135 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT SITE 853 FT /note="Critical for replication fidelity and mismatch FT recognition" FT /evidence="ECO:0000269|PubMed:37202477" FT SITE 1102 FT /note="Critical for replication fidelity and mismatch FT recognition" FT /evidence="ECO:0000269|PubMed:37202477" FT VARIANT 3 FT /note="R -> P (in PEOB1 and SANDO; dbSNP:rs121918045)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:12565911" FT /id="VAR_012153" FT VARIANT 18 FT /note="P -> S (in dbSNP:rs3087373)" FT /id="VAR_014904" FT VARIANT 55 FT /note="Q -> QQ" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_019265" FT VARIANT 55 FT /note="Q -> QQQ" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_019266" FT VARIANT 193 FT /note="R -> Q (in dbSNP:rs3176162)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_019267" FT VARIANT 227 FT /note="R -> W (in PEOB1 and MTDPS4B; dbSNP:rs121918056)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:15349879, ECO:0000269|PubMed:19307547" FT /id="VAR_023663" FT VARIANT 232 FT /note="R -> G (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:15689359" FT /id="VAR_058870" FT VARIANT 232 FT /note="R -> H (in LS; displays markedly increased FT exonuclease activity and reduced polymerization activity; FT produces ligatable 5'-ends; dbSNP:rs113994093)" FT /evidence="ECO:0000269|PubMed:18828154, FT ECO:0000269|PubMed:26095671" FT /id="VAR_058871" FT VARIANT 244 FT /note="L -> P (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:15689359" FT /id="VAR_058872" FT VARIANT 251 FT /note="T -> I (in PEOB1, MTDPS4A and MTDPS4B; FT dbSNP:rs113994094)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:12825077, FT ECO:0000269|PubMed:14635118, ECO:0000269|PubMed:18828154" FT /id="VAR_023664" FT VARIANT 268 FT /note="G -> A (in PEOB1; sporadic case; displays mildly FT reduced exonuclease activity; does not affect the FT polymerization activity or 5'-end ligation; FT dbSNP:rs61752784)" FT /evidence="ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:26095671" FT /id="VAR_058873" FT VARIANT 275 FT /note="R -> Q (found in a patient with epileptic FT encephalopathy, developmental delay and moderate FT intellectual disability; uncertain significance; displays FT mildly reduced exonuclease activity; reduced polymerization FT activity; reduced DNA-binding affinity; does not affect 5'- FT end ligation; dbSNP:rs1555453950)" FT /evidence="ECO:0000269|PubMed:26095671, FT ECO:0000269|PubMed:30552426" FT /id="VAR_088657" FT VARIANT 277 FT /note="H -> L (in PEOB1; uncertain significance; does not FT affect exonuclease activity; does not affect polymerization FT activity; does not affect 5'-end ligation; FT dbSNP:rs138929605)" FT /evidence="ECO:0000269|PubMed:21301859, FT ECO:0000269|PubMed:26095671" FT /id="VAR_088658" FT VARIANT 303 FT /note="G -> R (in MTDPS4A; likely pathogenic; results in FT loss of exonuclease activity and formation of an FT unligatable 5'-flap; displays low polymerization activity FT and reduced DNA-binding affinity; dbSNP:rs749799663)" FT /evidence="ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:26095671" FT /id="VAR_088659" FT VARIANT 304 FT /note="L -> R (in PEOB1 and SANDO; results in loss of FT exonuclease activity and formation of an unligatable 5'- FT flap; displays low polymerization activity and reduced DNA- FT binding affinity; dbSNP:rs121918044)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:26095671" FT /id="VAR_012154" FT VARIANT 304 FT /note="L -> SANDO (in PEOB1)" FT /id="VAR_058874" FT VARIANT 305 FT /note="S -> R (in MTDPS4A; likely pathogenic; results in FT loss of exonuclease activity and formation of an FT unligatable 5'-flap; displays low polymerization activity FT and reduced DNA-binding affinity; dbSNP:rs769410130)" FT /evidence="ECO:0000269|PubMed:22000311, FT ECO:0000269|PubMed:26095671" FT /id="VAR_088660" FT VARIANT 308 FT /note="Q -> H (in PEOB1; sporadic case; dbSNP:rs745539599)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058875" FT VARIANT 309 FT /note="R -> L (in PEOB1)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:15349879" FT /id="VAR_023665" FT VARIANT 312 FT /note="W -> R (in PEOB1; sporadic case)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:14635118" FT /id="VAR_023666" FT VARIANT 324 FT /note="P -> S (in dbSNP:rs2307437)" FT /id="VAR_014905" FT VARIANT 380 FT /note="G -> D (in PEOB1)" FT /evidence="ECO:0000269|PubMed:16639411" FT /id="VAR_058876" FT VARIANT 431 FT /note="G -> V (in PEOB1; sporadic case)" FT /evidence="ECO:0000269|PubMed:12707443" FT /id="VAR_023667" FT VARIANT 463 FT /note="L -> F (in dbSNP:rs150828914)" FT /evidence="ECO:0000269|PubMed:17420318" FT /id="VAR_058877" FT VARIANT 467 FT /note="A -> T (in PEOB1, SANDO, SCAE and MTDPS4A; FT pathogenic; results in clearly decreased activity, DNA FT binding and processivity of the polymerase; FT dbSNP:rs113994095)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:14635118, ECO:0000269|PubMed:14694057, FT ECO:0000269|PubMed:15122711, ECO:0000269|PubMed:15477547, FT ECO:0000269|PubMed:15689359, ECO:0000269|PubMed:15824347, FT ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:18828154, ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:22000311, ECO:0000269|PubMed:26942291" FT /id="VAR_012155" FT VARIANT 468 FT /note="N -> D (in PEOB1; dbSNP:rs145843073)" FT /evidence="ECO:0000269|PubMed:15351195" FT /id="VAR_023668" FT VARIANT 497 FT /note="Q -> H (in SANDO and SCAE; dbSNP:rs121918052)" FT /evidence="ECO:0000269|PubMed:15824347, FT ECO:0000269|PubMed:26942291" FT /id="VAR_023669" FT VARIANT 511 FT /note="S -> N (in PEOA1; dbSNP:rs121918055)" FT /evidence="ECO:0000269|PubMed:17420318" FT /id="VAR_058878" FT VARIANT 517 FT /note="G -> V (in SANDO; dbSNP:rs61752783)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058879" FT VARIANT 546 FT /note="R -> C (in dbSNP:rs2307447)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_014906" FT VARIANT 562 FT /note="R -> Q (in PEOB1; sporadic case; dbSNP:rs781168350)" FT /evidence="ECO:0000269|PubMed:14635118" FT /id="VAR_058880" FT VARIANT 574 FT /note="R -> W (in PEOB1; sporadic case; dbSNP:rs774474723)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058881" FT VARIANT 579 FT /note="R -> W (in PEOB1; dbSNP:rs556925652)" FT /evidence="ECO:0000269|PubMed:12975295" FT /id="VAR_023670" FT VARIANT 587 FT /note="P -> L (in PEOB1, MTDPS4A and MTDPS4B; FT dbSNP:rs113994096)" FT /evidence="ECO:0000269|PubMed:12825077, FT ECO:0000269|PubMed:12975295, ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:15349879, ECO:0000269|PubMed:15689359, FT ECO:0000269|PubMed:18828154" FT /id="VAR_023671" FT VARIANT 603 FT /note="M -> L (in PEOB1)" FT /evidence="ECO:0000269|PubMed:16401742" FT /id="VAR_058882" FT VARIANT 627 FT /note="R -> Q (in SANDO; shows DNA binding affinity and FT processivities similar to the controls; dbSNP:rs375305567)" FT /evidence="ECO:0000269|PubMed:15917273" FT /id="VAR_058883" FT VARIANT 627 FT /note="R -> W (in SANDO; sporadic case; dbSNP:rs121918046)" FT /evidence="ECO:0000269|PubMed:12565911" FT /id="VAR_023672" FT VARIANT 648 FT /note="P -> R (in PEOB1; sporadic case; also in SANDO; FT dbSNP:rs796052906)" FT /evidence="ECO:0000269|PubMed:16621917, FT ECO:0000269|PubMed:16919951" FT /id="VAR_058884" FT VARIANT 662 FT /note="E -> K (in dbSNP:rs2307450)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_014907" FT VARIANT 737 FT /note="G -> R (in PEOB1; with absence of progressive FT external ophthalmoplegia; dbSNP:rs121918054)" FT /evidence="ECO:0000269|PubMed:16634032" FT /id="VAR_058885" FT VARIANT 748 FT /note="W -> S (in SANDO, SCAE and MTDPS4A; pathogenic; FT dbSNP:rs113994097)" FT /evidence="ECO:0000269|PubMed:15477547, FT ECO:0000269|PubMed:15824347, ECO:0000269|PubMed:15929042, FT ECO:0000269|PubMed:16080118, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:18828154, ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:22000311, ECO:0000269|PubMed:26942291" FT /id="VAR_023673" FT VARIANT 767 FT /note="A -> D (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058886" FT VARIANT 807 FT /note="R -> C (in SANDO; dbSNP:rs769827124)" FT /evidence="ECO:0000269|PubMed:16919951" FT /id="VAR_058887" FT VARIANT 807 FT /note="R -> P (in PEOB1; sporadic case)" FT /evidence="ECO:0000269|PubMed:14635118" FT /id="VAR_058888" FT VARIANT 831 FT /note="Y -> C (in PEOA1 and MTDPS4A; uncertain FT significance; dbSNP:rs41549716)" FT /evidence="ECO:0000269|PubMed:15534189, FT ECO:0000269|PubMed:17846414, ECO:0000269|PubMed:18828154" FT /id="VAR_023674" FT VARIANT 848 FT /note="G -> S (in PEOB1, MTDPS4A, MTDPS4B and LS; also FT found in a patient with epileptic encephalopathy, FT developmental delay and moderate intellectual disability; FT dbSNP:rs113994098)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:12872260, ECO:0000269|PubMed:15689359, FT ECO:0000269|PubMed:15929042, ECO:0000269|PubMed:18828154, FT ECO:0000269|PubMed:19307547, ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:22000311, ECO:0000269|PubMed:30552426" FT /id="VAR_023675" FT VARIANT 852 FT /note="R -> C (in MTDPS4A; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:22000311" FT /id="VAR_088688" FT VARIANT 853 FT /note="R -> W (in PEOB1; with absence of progressive FT external ophthalmoplegia; dbSNP:rs121918053)" FT /evidence="ECO:0000269|PubMed:16401742, FT ECO:0000269|PubMed:16634032" FT /id="VAR_058889" FT VARIANT 864 FT /note="N -> S (in MTDPS4B; dbSNP:rs121918050)" FT /evidence="ECO:0000269|PubMed:12825077" FT /id="VAR_023676" FT VARIANT 879 FT /note="Q -> H (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058890" FT VARIANT 885 FT /note="T -> S (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058891" FT VARIANT 889 FT /note="A -> T (in PEOB1; dbSNP:rs763393580)" FT /evidence="ECO:0000269|PubMed:12975295" FT /id="VAR_023677" FT VARIANT 914 FT /note="T -> P (in MTDPS4A; dbSNP:rs139590686)" FT /evidence="ECO:0000269|PubMed:16621917, FT ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18828154" FT /id="VAR_058892" FT VARIANT 923 FT /note="G -> D (in PEOA1)" FT /evidence="ECO:0000269|PubMed:12210792" FT /id="VAR_023678" FT VARIANT 932 FT /note="H -> Y (in SANDO and PEOB1; sporadic case; FT dbSNP:rs121918048)" FT /evidence="ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:14745080" FT /id="VAR_023679" FT VARIANT 943 FT /note="R -> C (in PEOB1; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:21301859" FT /id="VAR_088689" FT VARIANT 943 FT /note="R -> H (in PEOA1)" FT /evidence="ECO:0000269|PubMed:12210792" FT /id="VAR_023680" FT VARIANT 953 FT /note="R -> C (in PEOA1; dbSNP:rs11546842)" FT /evidence="ECO:0000269|PubMed:15351195" FT /id="VAR_023681" FT VARIANT 955 FT /note="Y -> C (in PEOA1, PEOB1 and SANDO; 45-fold decrease FT in apparent binding affinity for the incoming nucleoside FT triphosphate; 2-fold less accurate for basepair FT substitutions than wild-type; dbSNP:rs113994099)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:15351195" FT /id="VAR_012156" FT VARIANT 957 FT /note="A -> P (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:15689359" FT /id="VAR_058893" FT VARIANT 957 FT /note="A -> S (in PEOA1; dbSNP:rs121918051)" FT /evidence="ECO:0000269|PubMed:12210792" FT /id="VAR_023682" FT VARIANT 966 FT /note="L -> R (in MTDPS4A; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:22000311" FT /id="VAR_088690" FT VARIANT 1047 FT /note="R -> Q (in PEOB1; sporadic case; dbSNP:rs768028281)" FT /evidence="ECO:0000269|PubMed:12707443" FT /id="VAR_023683" FT VARIANT 1051 FT /note="G -> R (in SANDO; dbSNP:rs121918049)" FT /evidence="ECO:0000269|PubMed:14745080" FT /id="VAR_023684" FT VARIANT 1076 FT /note="G -> V (in PEOB1)" FT /evidence="ECO:0000269|PubMed:12975295" FT /id="VAR_023685" FT VARIANT 1096 FT /note="R -> C (in PEOB1 and MTDPS4A; dbSNP:rs201732356)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:25129007" FT /id="VAR_023686" FT VARIANT 1096 FT /note="R -> H (in MTDPS4A; dbSNP:rs368435864)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058894" FT VARIANT 1104 FT /note="S -> C (in PEOB1; sporadic case; FT dbSNP:rs1010372555)" FT /evidence="ECO:0000269|PubMed:12707443" FT /id="VAR_023687" FT VARIANT 1105 FT /note="A -> T (in PEOB1; dbSNP:rs753410045)" FT /evidence="ECO:0000269|PubMed:15351195" FT /id="VAR_023688" FT VARIANT 1106 FT /note="V -> I (in PEOB1)" FT /evidence="ECO:0000269|PubMed:15349879" FT /id="VAR_023689" FT VARIANT 1110 FT /note="H -> Y (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:18828154" FT /id="VAR_058895" FT VARIANT 1134 FT /note="H -> R (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:18828154" FT /id="VAR_058896" FT VARIANT 1136 FT /note="E -> K (in MTDPS4A; dbSNP:rs56047213)" FT /evidence="ECO:0000269|PubMed:18828154" FT /id="VAR_065092" FT VARIANT 1142 FT /note="R -> W (in dbSNP:rs2307442)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_014908" FT VARIANT 1143 FT /note="E -> G (in dbSNP:rs2307441)" FT /evidence="ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15689359, FT ECO:0000269|PubMed:16080118, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:18828154, ECO:0000269|Ref.4" FT /id="VAR_014909" FT VARIANT 1146 FT /note="R -> C (in PEOB1; uncertain significance; FT dbSNP:rs2307440)" FT /evidence="ECO:0000269|PubMed:16401742, ECO:0000269|Ref.4" FT /id="VAR_014910" FT VARIANT 1176 FT /note="S -> L (in PEOA1; dbSNP:rs776031396)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:15349879" FT /id="VAR_023690" FT VARIANT 1184 FT /note="D -> N (in PEOB1; dbSNP:rs1131691575)" FT /evidence="ECO:0000269|PubMed:16401742" FT /id="VAR_058897" FT VARIANT 1186 FT /note="D -> H (in PEOA1)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065119" FT VARIANT 1191 FT /note="K -> N (in MTDPS4A; dbSNP:rs1085307741)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058898" FT VARIANT 1236 FT /note="Q -> H (in dbSNP:rs3087374)" FT /evidence="ECO:0000269|PubMed:12975295, FT ECO:0000269|PubMed:14635118, ECO:0000269|PubMed:15917273, FT ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18828154, FT ECO:0000269|Ref.4" FT /id="VAR_014911" FT MUTAGEN 198 FT /note="D->A: Abolishes exonuclease activity; when FT associated with A-200. Decreases polymerase exonucleolytic FT proofreading by 30-fold for the T:G mismatch and by 14-fold FT for the A:A mismatch; when associated with A-200. FT Significantly increases mitochondrial DNA mutation FT frequency. Does not affect DNA polymerase activity." FT /evidence="ECO:0000269|PubMed:10827171, FT ECO:0000269|PubMed:11504725, ECO:0000269|PubMed:37202477" FT MUTAGEN 200 FT /note="E->A: Abolishes exonuclease activity; when FT associated with A-198. Decreases polymerase exonucleolytic FT proofreading by 30-fold for the T:G mismatch and by 14-fold FT for the A:A mismatch; when associated with A-198." FT /evidence="ECO:0000269|PubMed:11477093, FT ECO:0000269|PubMed:11504725, ECO:0000269|PubMed:37202477" FT MUTAGEN 274 FT /note="D->A: Unable to idle at the 5'-end of the nascent FT DNA strand. Continues DNA synthesis into double-stranded FT DNA past the 5'-end creating a flap structure that cannot FT be ligated." FT /evidence="ECO:0000269|PubMed:26095671" FT MUTAGEN 498 FT /note="K->C: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:26056153" FT MUTAGEN 499 FT /note="K->C: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:26056153" FT MUTAGEN 501 FT /note="K->C: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:26056153" FT MUTAGEN 543..558 FT /note="Missing: Markedly decreases the stimulation by FT POLG2, resulting in impaired processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 549 FT /note="L->N: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 552 FT /note="L->N: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 553 FT /note="K->N: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 853 FT /note="R->A: Abolishes primer DNA extention in the presence FT of dNTPs. Impairs intrinsic polymerase processivity. FT Enhances exonuclease activity leading to primer DNA FT degradation." FT /evidence="ECO:0000269|PubMed:37202477" FT MUTAGEN 890 FT /note="D->N: Abolishes DNA polymerase activity." FT /evidence="ECO:0000269|PubMed:10827171" FT MUTAGEN 1135 FT /note="D->N: Abolishes DNA polymerase activity." FT /evidence="ECO:0000269|PubMed:10827171" FT HELIX 73..75 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 76..78 FT /evidence="ECO:0007829|PDB:8D42" FT HELIX 81..87 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 97..110 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 114..116 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 135..157 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 172..178 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 180..182 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 184..186 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 193..200 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 203..205 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 207..210 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 211..215 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 220..224 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 226..229 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 237..239 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 241..243 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 248..251 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 254..256 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 260..262 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 265..270 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 271..275 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 279..282 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 283..285 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 290..293 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 294..300 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 306..314 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 347..350 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 356..363 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 376..379 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 382..387 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 389..417 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 421..430 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 435..438 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 440..470 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 471..481 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 483..487 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 503..505 FT /evidence="ECO:0007829|PDB:5C51" FT STRAND 519..521 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 538..553 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 554..558 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 559..561 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 567..569 FT /evidence="ECO:0007829|PDB:8D37" FT HELIX 571..575 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 587..589 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 594..598 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 599..602 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 606..609 FT /evidence="ECO:0007829|PDB:8V5R" FT STRAND 610..615 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 616..618 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 619..624 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 628..630 FT /evidence="ECO:0007829|PDB:8D37" FT HELIX 636..644 FT /evidence="ECO:0007829|PDB:3IKM" FT TURN 648..650 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 651..662 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 716..721 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 739..742 FT /evidence="ECO:0007829|PDB:8D3R" FT STRAND 743..745 FT /evidence="ECO:0007829|PDB:4ZTU" FT STRAND 748..751 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 755..757 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 765..767 FT /evidence="ECO:0007829|PDB:8V5R" FT HELIX 768..770 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 771..775 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 778..780 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 782..784 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 787..809 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 814..816 FT /evidence="ECO:0007829|PDB:8D42" FT HELIX 818..820 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 823..826 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 833..835 FT /evidence="ECO:0007829|PDB:8V5R" FT STRAND 837..840 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 845..848 FT /evidence="ECO:0007829|PDB:4ZTU" FT TURN 849..851 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 853..855 FT /evidence="ECO:0007829|PDB:4ZTU" FT HELIX 859..861 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 867..869 FT /evidence="ECO:0007829|PDB:8D37" FT HELIX 872..877 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 884..890 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 894..907 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 909..911 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 915..922 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 925..928 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 931..938 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 943..954 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 959..969 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 971..973 FT /evidence="ECO:0007829|PDB:8V5D" FT HELIX 975..989 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 991..993 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 997..999 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 1001..1009 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 1010..1013 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 1027..1030 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 1033..1035 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 1037..1040 FT /evidence="ECO:0007829|PDB:3IKM" FT TURN 1041..1046 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 1050..1052 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1055..1066 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1067..1069 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 1073..1075 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1081..1083 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 1085..1087 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1089..1092 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 1093..1122 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1127..1132 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1134..1142 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1143..1145 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1146..1167 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1175..1177 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1183..1188 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1191..1194 FT /evidence="ECO:0007829|PDB:8D33" FT STRAND 1202..1204 FT /evidence="ECO:0007829|PDB:8D33" FT HELIX 1206..1209 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1216..1218 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1220..1227 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1232..1235 FT /evidence="ECO:0007829|PDB:3IKM" SQ SEQUENCE 1239 AA; 139562 MW; 2D9ECCD75AD6E01E CRC64; MSRLLWRKVA GATVGPGPVP APGRWVSSSV PASDPSDGQR RRQQQQQQQQ QQQQQPQQPQ VLSSEGGQLR HNPLDIQMLS RGLHEQIFGQ GGEMPGEAAV RRSVEHLQKH GLWGQPAVPL PDVELRLPPL YGDNLDQHFR LLAQKQSLPY LEAANLLLQA QLPPKPPAWA WAEGWTRYGP EGEAVPVAIP EERALVFDVE VCLAEGTCPT LAVAISPSAW YSWCSQRLVE ERYSWTSQLS PADLIPLEVP TGASSPTQRD WQEQLVVGHN VSFDRAHIRE QYLIQGSRMR FLDTMSMHMA ISGLSSFQRS LWIAAKQGKH KVQPPTKQGQ KSQRKARRGP AISSWDWLDI SSVNSLAEVH RLYVGGPPLE KEPRELFVKG TMKDIRENFQ DLMQYCAQDV WATHEVFQQQ LPLFLERCPH PVTLAGMLEM GVSYLPVNQN WERYLAEAQG TYEELQREMK KSLMDLANDA CQLLSGERYK EDPWLWDLEW DLQEFKQKKA KKVKKEPATA SKLPIEGAGA PGDPMDQEDL GPCSEEEEFQ QDVMARACLQ KLKGTTELLP KRPQHLPGHP GWYRKLCPRL DDPAWTPGPS LLSLQMRVTP KLMALTWDGF PLHYSERHGW GYLVPGRRDN LAKLPTGTTL ESAGVVCPYR AIESLYRKHC LEQGKQQLMP QEAGLAEEFL LTDNSAIWQT VEELDYLEVE AEAKMENLRA AVPGQPLALT ARGGPKDTQP SYHHGNGPYN DVDIPGCWFF KLPHKDGNSC NVGSPFAKDF LPKMEDGTLQ AGPGGASGPR ALEINKMISF WRNAHKRISS QMVVWLPRSA LPRAVIRHPD YDEEGLYGAI LPQVVTAGTI TRRAVEPTWL TASNARPDRV GSELKAMVQA PPGYTLVGAD VDSQELWIAA VLGDAHFAGM HGCTAFGWMT LQGRKSRGTD LHSKTATTVG ISREHAKIFN YGRIYGAGQP FAERLLMQFN HRLTQQEAAE KAQQMYAATK GLRWYRLSDE GEWLVRELNL PVDRTEGGWI SLQDLRKVQR ETARKSQWKK WEVVAERAWK GGTESEMFNK LESIATSDIP RTPVLGCCIS RALEPSAVQE EFMTSRVNWV VQSSAVDYLH LMLVAMKWLF EEFAIDGRFC ISIHDEVRYL VREEDRYRAA LALQITNLLT RCMFAYKLGL NDLPQSVAFF SAVDIDRCLR KEVTMDCKTP SNPTGMERRY GIPQGEALDI YQIIELTKGS LEKRSQPGP // ID DPOG2_HUMAN Reviewed; 485 AA. AC Q9UHN1; O00419; Q0IJ81; Q96GW2; Q9UK35; Q9UK94; DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 28-JAN-2026, entry version 201. DE RecName: Full=DNA polymerase subunit gamma-2; DE AltName: Full=DNA polymerase gamma accessory 55 kDa subunit; DE Short=p55 {ECO:0000303|PubMed:10608893}; DE AltName: Full=Mitochondrial DNA polymerase accessory subunit; DE AltName: Full=MtPolB; DE AltName: Full=PolG-beta; DE Flags: Precursor; GN Name=POLG2 {ECO:0000303|PubMed:30157269, ECO:0000312|HGNC:HGNC:9180}; GN Synonyms=MTPOLB; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Cerebellum; RX PubMed=10608893; DOI=10.1074/jbc.274.53.38197; RA Lim S.E., Longley M.J., Copeland W.C.; RT "The mitochondrial p55 accessory subunit of human DNA polymerase gamma RT enhances DNA binding, promotes processive DNA synthesis, and confers N- RT ethylmaleimide resistance."; RL J. Biol. Chem. 274:38197-38203(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-169. RX PubMed=10666468; DOI=10.1093/nar/28.5.1237; RA Carrodeguas J.A., Bogenhagen D.F.; RT "Protein sequences conserved in prokaryotic aminoacyl-tRNA synthetases are RT important for the activity of the processivity factor of human RT mitochondrial DNA polymerase."; RL Nucleic Acids Res. 28:1237-1244(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=10677218; DOI=10.1021/bi992104w; RA Johnson A.A., Tsai Y.-C., Graves S.W., Johnson K.A.; RT "Human mitochondrial DNA polymerase holoenzyme: reconstitution and RT characterization."; RL Biochemistry 39:1702-1708(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS THR-169 AND ALA-416. RC TISSUE=Cervix, and Ovary; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] OF 114-485. RX PubMed=9153213; DOI=10.1074/jbc.272.21.13640; RA Wang Y., Farr C.L., Kaguni L.S.; RT "Accessory subunit of mitochondrial DNA polymerase from Drosophila embryos. RT Cloning, molecular analysis, and association in the native enzyme."; RL J. Biol. Chem. 272:13640-13646(1997). RN [6] RP FUNCTION, AND SUBUNIT. RX PubMed=11477093; DOI=10.1074/jbc.m106045200; RA Johnson A.A., Johnson K.A.; RT "Fidelity of nucleotide incorporation by human mitochondrial DNA RT polymerase."; RL J. Biol. Chem. 276:38090-38096(2001). RN [7] RP FUNCTION, AND SUBUNIT. RX PubMed=11477094; DOI=10.1074/jbc.m106046200; RA Johnson A.A., Johnson K.A.; RT "Exonuclease proofreading by human mitochondrial DNA polymerase."; RL J. Biol. Chem. 276:38097-38107(2001). RN [8] RP FUNCTION, AND SUBUNIT. RX PubMed=11504725; DOI=10.1074/jbc.m105230200; RA Longley M.J., Nguyen D., Kunkel T.A., Copeland W.C.; RT "The fidelity of human DNA polymerase gamma with and without exonucleolytic RT proofreading and the p55 accessory subunit."; RL J. Biol. Chem. 276:38555-38562(2001). RN [9] RP FUNCTION, AND SUBUNIT. RX PubMed=15167897; DOI=10.1038/sj.emboj.7600257; RA Korhonen J.A., Pham X.H., Pellegrini M., Falkenberg M.; RT "Reconstitution of a minimal mtDNA replisome in vitro."; RL EMBO J. 23:2423-2429(2004). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-38, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [12] RP FUNCTION, AND CHARACTERIZATION OF VARIANT MTDPS16 TRP-182. RX PubMed=30157269; DOI=10.1371/journal.pone.0203198; RA Hoff K.E., DeBalsi K.L., Sanchez-Quintero M.J., Longley M.J., Hirano M., RA Naini A.B., Copeland W.C.; RT "Characterization of the human homozygous R182W POLG2 mutation in RT mitochondrial DNA depletion syndrome."; RL PLoS ONE 13:e0203198-e0203198(2018). RN [13] RP X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) OF 1-146 AND 181-485, FUNCTION, AND RP SUBUNIT. RX PubMed=19837034; DOI=10.1016/j.cell.2009.07.050; RA Lee Y.S., Kennedy W.D., Yin Y.W.; RT "Structural insight into processive human mitochondrial DNA synthesis and RT disease-related polymerase mutations."; RL Cell 139:312-324(2009). RN [14] RP X-RAY CRYSTALLOGRAPHY (3.30 ANGSTROMS) OF 26-485, FUNCTION, AND SUBUNIT. RX PubMed=26056153; DOI=10.15252/embj.201591520; RA Szymanski M.R., Kuznetsov V.B., Shumate C., Meng Q., Lee Y.S., Patel G., RA Patel S., Yin Y.W.; RT "Structural basis for processivity and antiviral drug toxicity in human RT mitochondrial DNA replicase."; RL EMBO J. 34:1959-1970(2015). RN [15] RP STRUCTURE BY ELECTRON MICROSCOPY (2.46 ANGSTROMS), FUNCTION, AND SUBUNIT. RX PubMed=37202477; DOI=10.1038/s41594-023-00980-2; RA Park J., Herrmann G.K., Mitchell P.G., Sherman M.B., Yin Y.W.; RT "Polgamma coordinates DNA synthesis and proofreading to ensure RT mitochondrial genome integrity."; RL Nat. Struct. Mol. Biol. 30:812-823(2023). RN [16] RP VARIANT PEOA4 GLU-451, AND CHARACTERIZATION OF VARIANT PEOA4 GLU-451. RX PubMed=16685652; DOI=10.1086/504303; RA Longley M.J., Clark S., Man C.Y.W., Hudson G., Durham S.E., Taylor R.W., RA Nightingale S., Turnbull D.M., Copeland W.C., Chinnery P.F.; RT "Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive RT external ophthalmoplegia."; RL Am. J. Hum. Genet. 78:1026-1034(2006). RN [17] RP VARIANT ALA-416, AND CHARACTERIZATION OF VARIANT ALA-416. RX PubMed=18195150; DOI=10.1001/archneurol.2007.9; RA Ferraris S., Clark S., Garelli E., Davidzon G., Moore S.A., Kardon R.H., RA Bienstock R.J., Longley M.J., Mancuso M., Gutierrez Rios P., Hirano M., RA Copeland W.C., DiMauro S.; RT "Progressive external ophthalmoplegia and vision and hearing loss in a RT patient with mutations in POLG2 and OPA1."; RL Arch. Neurol. 65:125-131(2008). RN [18] RP VARIANT MTDPS16 TRP-182, AND INVOLVEMENT IN MTDPS16. RX PubMed=27592148; DOI=10.1016/j.ejmg.2016.08.012; RA Varma H., Faust P.L., Iglesias A.D., Lagana S.M., Wou K., Hirano M., RA DiMauro S., Mansukani M.M., Hoff K.E., Nagy P.L., Copeland W.C., RA Naini A.B.; RT "Whole exome sequencing identifies a homozygous POLG2 missense variant in RT an infant with fulminant hepatic failure and mitochondrial DNA depletion."; RL Eur. J. Med. Genet. 59:540-545(2016). RN [19] RP VARIANT MTDPS16B TYR-433, INVOLVEMENT IN MTDPS16B, CHARACTERIZATION OF RP VARIANT MTDPS16B TYR-433, AND FUNCTION. RX PubMed=31778857; DOI=10.1016/j.ejmg.2019.103821; RA Dosekova P., Dubiel A., Karlowicz A., Zietkiewicz S., Rydzanicz M., RA Habalova V., Pienkowski V.M., Skirkova M., Han V., Mosejova A., RA Gdovinova Z., Kaliszewska M., Tonska K., Szymanski M.R., Skorvanek M., RA Ploski R.; RT "Whole exome sequencing identifies a homozygous POLG2 missense variant in RT an adult patient presenting with optic atrophy, movement disorders, RT premature ovarian failure and mitochondrial DNA depletion."; RL Eur. J. Med. Genet. 63:103821-103821(2020). CC -!- FUNCTION: Accessory subunit of DNA polymerase gamma solely responsible CC for replication of mitochondrial DNA (mtDNA). Acts as an allosteric CC regulator of the holoenzyme activities. Enhances the polymerase CC activity and the processivity of POLG by increasing its interactions CC with the DNA template. Suppresses POLG exonucleolytic proofreading CC especially toward homopolymeric templates bearing mismatched termini. CC Binds to single-stranded DNA. {ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11504725, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26056153, ECO:0000269|PubMed:30157269, CC ECO:0000269|PubMed:31778857, ECO:0000269|PubMed:37202477}. CC -!- SUBUNIT: Heterotrimer composed of a catalytic subunit and a homodimer CC of accessory subunits (POLG:POLG2). {ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11504725, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26056153, ECO:0000269|PubMed:37202477}. CC -!- INTERACTION: CC Q9UHN1; P54098: POLG; NbExp=15; IntAct=EBI-852642, EBI-852624; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:P54098}. CC Mitochondrion matrix, mitochondrion nucleoid CC {ECO:0000250|UniProtKB:P54098}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 4 (PEOA4) [MIM:610131]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:16685652}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 16, hepatic type CC (MTDPS16) [MIM:618528]: An autosomal recessive disorder characterized CC by poor feeding, difficulty breathing, abdominal distention, an CC abnormal carnitine profile, metabolic acidosis and hepatic failure in CC the neonatal period. Severe mtDNA depletion is observed in liver and CC muscle biopsies. {ECO:0000269|PubMed:27592148, CC ECO:0000269|PubMed:30157269}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 16B, neuroophthalmic type CC (MTDPS16B) [MIM:619425]: An autosomal recessive disorder characterized CC by childhood onset of progressive neuroophthalmic manifestations with CC optic atrophy, mixed polyneuropathy, spinal and cerebellar ataxia, and CC generalized chorea associated with mtDNA depletion. CC {ECO:0000269|PubMed:31778857}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF142992; AAD50382.1; -; mRNA. DR EMBL; AF177201; AAD56640.1; -; mRNA. DR EMBL; AF184344; AAD56542.1; -; mRNA. DR EMBL; BC000913; AAH00913.2; -; mRNA. DR EMBL; BC009194; AAH09194.1; -; mRNA. DR EMBL; U94703; AAC51321.1; -; mRNA. DR CCDS; CCDS32706.1; -. DR RefSeq; NP_009146.2; NM_007215.4. DR PDB; 2G4C; X-ray; 3.15 A; A/B/C/D=26-485. DR PDB; 3IKL; X-ray; 3.10 A; A/B=1-146, A/B=181-485. DR PDB; 3IKM; X-ray; 3.24 A; B/C/E/F=59-485. DR PDB; 4ZTU; X-ray; 3.30 A; B/C=26-485. DR PDB; 4ZTZ; X-ray; 3.44 A; B/C=26-485. DR PDB; 5C51; X-ray; 3.43 A; B/C=1-485. DR PDB; 5C52; X-ray; 3.64 A; B/C=1-485. DR PDB; 5C53; X-ray; 3.57 A; B/C=1-485. DR PDB; 8D33; EM; 2.46 A; B/C=1-485. DR PDB; 8D37; EM; 2.65 A; B/C=1-485. DR PDB; 8D3R; EM; 3.04 A; B/C=1-485. DR PDB; 8D42; EM; 2.91 A; B/C=1-485. DR PDB; 8G5I; EM; 2.75 A; B/C=1-485. DR PDB; 8G5J; EM; 2.63 A; B/C=1-485. DR PDB; 8G5K; EM; 2.90 A; B/C=1-485. DR PDB; 8G5L; EM; 3.00 A; B/C=1-485. DR PDB; 8G5M; EM; 2.58 A; B/C=1-485. DR PDB; 8G5N; EM; 2.73 A; B/C=1-485. DR PDB; 8G5O; EM; 2.61 A; B/C=1-485. DR PDB; 8G5P; EM; 2.78 A; B/C=1-485. DR PDB; 8T7E; EM; 3.08 A; B/C=1-485. DR PDB; 8UDK; X-ray; 3.43 A; B/C=1-485. DR PDB; 8UDL; EM; 2.37 A; B/C=1-485. DR PDB; 8V54; EM; 4.10 A; B/C=26-485. DR PDB; 8V55; EM; 4.20 A; B/C=26-485. DR PDB; 8V5R; EM; 3.00 A; B/C=26-485. DR PDB; 9GGB; EM; 2.63 A; B/C=25-485. DR PDB; 9GGC; EM; 2.39 A; B/C=25-485. DR PDB; 9GGD; EM; 2.67 A; B/C=25-485. DR PDB; 9GGE; EM; 2.69 A; B/C=25-485. DR PDB; 9GGF; EM; 2.65 A; B/C=25-485. DR PDB; 9IBX; EM; 2.54 A; B/C=25-485. DR PDB; 9IBZ; EM; 3.08 A; B/C=25-485. DR PDB; 9IC0; EM; 3.24 A; B/C=25-485. DR PDBsum; 2G4C; -. DR PDBsum; 3IKL; -. DR PDBsum; 3IKM; -. DR PDBsum; 4ZTU; -. DR PDBsum; 4ZTZ; -. DR PDBsum; 5C51; -. DR PDBsum; 5C52; -. DR PDBsum; 5C53; -. DR PDBsum; 8D33; -. DR PDBsum; 8D37; -. DR PDBsum; 8D3R; -. DR PDBsum; 8D42; -. DR PDBsum; 8G5I; -. DR PDBsum; 8G5J; -. DR PDBsum; 8G5K; -. DR PDBsum; 8G5L; -. DR PDBsum; 8G5M; -. DR PDBsum; 8G5N; -. DR PDBsum; 8G5O; -. DR PDBsum; 8G5P; -. DR PDBsum; 8T7E; -. DR PDBsum; 8UDK; -. DR PDBsum; 8UDL; -. DR PDBsum; 8V54; -. DR PDBsum; 8V55; -. DR PDBsum; 8V5R; -. DR PDBsum; 9GGB; -. DR PDBsum; 9GGC; -. DR PDBsum; 9GGD; -. DR PDBsum; 9GGE; -. DR PDBsum; 9GGF; -. DR PDBsum; 9IBX; -. DR PDBsum; 9IBZ; -. DR PDBsum; 9IC0; -. DR AlphaFoldDB; Q9UHN1; -. DR EMDB; EMD-27154; -. DR EMDB; EMD-27155; -. DR EMDB; EMD-27163; -. DR EMDB; EMD-27172; -. DR EMDB; EMD-29745; -. DR EMDB; EMD-29746; -. DR EMDB; EMD-29747; -. DR EMDB; EMD-29748; -. DR EMDB; EMD-29749; -. DR EMDB; EMD-29750; -. DR EMDB; EMD-29751; -. DR EMDB; EMD-29752; -. DR EMDB; EMD-41091; -. DR EMDB; EMD-42150; -. DR EMDB; EMD-42842; -. DR EMDB; EMD-42979; -. DR EMDB; EMD-42980; -. DR EMDB; EMD-42984; -. DR EMDB; EMD-51326; -. DR EMDB; EMD-51327; -. DR EMDB; EMD-51328; -. DR EMDB; EMD-51329; -. DR EMDB; EMD-51330; -. DR EMDB; EMD-52815; -. DR EMDB; EMD-52819; -. DR EMDB; EMD-52823; -. DR SMR; Q9UHN1; -. DR BioGRID; 116398; 39. DR ComplexPortal; CPX-2093; Mitochondrial DNA polymerase gamma complex. DR FunCoup; Q9UHN1; 851. DR IntAct; Q9UHN1; 37. DR MINT; Q9UHN1; -. DR STRING; 9606.ENSP00000442563; -. DR ChEMBL; CHEMBL3430903; -. DR DrugBank; DB12151; Brincidofovir. DR iPTMnet; Q9UHN1; -. DR PhosphoSitePlus; Q9UHN1; -. DR BioMuta; POLG2; -. DR DMDM; 17367139; -. DR jPOST; Q9UHN1; -. DR MassIVE; Q9UHN1; -. DR PaxDb; 9606-ENSP00000442563; -. DR PeptideAtlas; Q9UHN1; -. DR ProteomicsDB; 84382; -. DR Pumba; Q9UHN1; -. DR Antibodypedia; 50586; 171 antibodies from 29 providers. DR DNASU; 11232; -. DR Ensembl; ENST00000539111.7; ENSP00000442563.2; ENSG00000256525.9. DR GeneID; 11232; -. DR KEGG; hsa:11232; -. DR MANE-Select; ENST00000539111.7; ENSP00000442563.2; NM_007215.4; NP_009146.2. DR UCSC; uc002jei.4; human. DR AGR; HGNC:9180; -. DR ClinPGx; PA33501; -. DR CTD; 11232; -. DR DisGeNET; 11232; -. DR GeneCards; POLG2; -. DR HGNC; HGNC:9180; POLG2. DR HPA; ENSG00000256525; Low tissue specificity. DR MalaCards; POLG2; -. DR MIM; 604983; gene. DR MIM; 610131; phenotype. DR MIM; 618528; phenotype. DR MIM; 619425; phenotype. DR OpenTargets; ENSG00000256525; -. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR VEuPathDB; HostDB:ENSG00000256525; -. DR eggNOG; KOG2298; Eukaryota. DR GeneTree; ENSGT00940000153759; -. DR HOGENOM; CLU_055833_0_0_1; -. DR InParanoid; Q9UHN1; -. DR OMA; WGQEVLE; -. DR OrthoDB; 57698at2759; -. DR PAN-GO; Q9UHN1; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q9UHN1; -. DR BRENDA; 2.7.7.7; 2681. DR PathwayCommons; Q9UHN1; -. DR Reactome; R-HSA-2151201; Transcriptional activation of mitochondrial biogenesis. DR Reactome; R-HSA-9913635; Strand-asynchronous mitochondrial DNA replication. DR SignaLink; Q9UHN1; -. DR SIGNOR; Q9UHN1; -. DR Agora; ENSG00000256525; -. DR BioGRID-ORCS; 11232; 326 hits in 1164 CRISPR screens. DR ChiTaRS; POLG2; human. DR EvolutionaryTrace; Q9UHN1; -. DR GeneWiki; POLG2; -. DR GenomeRNAi; 11232; -. DR Pharos; Q9UHN1; Tbio. DR PRO; PR:Q9UHN1; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; Q9UHN1; protein. DR Bgee; ENSG00000256525; Expressed in secondary oocyte and 177 other cell types or tissues. DR ExpressionAtlas; Q9UHN1; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005760; C:gamma DNA polymerase complex; IDA:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; IDA:ComplexPortal. DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:BHF-UCL. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0070182; F:DNA polymerase binding; IPI:UniProtKB. DR GO; GO:0030337; F:DNA polymerase processivity factor activity; IDA:UniProtKB. DR GO; GO:0003887; F:DNA-directed DNA polymerase activity; IEA:Ensembl. DR GO; GO:0003690; F:double-stranded DNA binding; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl. DR GO; GO:0006261; P:DNA-templated DNA replication; IDA:UniProtKB. DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl. DR GO; GO:0006264; P:mitochondrial DNA replication; IDA:FlyBase. DR GO; GO:0007005; P:mitochondrion organization; IEA:Ensembl. DR GO; GO:1900264; P:positive regulation of DNA-directed DNA polymerase activity; IDA:UniProtKB. DR CDD; cd02426; Pol_gamma_b_Cterm; 1. DR FunFam; 3.40.50.800:FF:000014; Putative dna polymerase subunit gamma-2 mitochondrial; 1. DR Gene3D; 3.40.50.800; Anticodon-binding domain; 1. DR Gene3D; 3.30.930.10; Bira Bifunctional Protein, Domain 2; 1. DR InterPro; IPR045864; aa-tRNA-synth_II/BPL/LPL. DR InterPro; IPR004154; Anticodon-bd. DR InterPro; IPR036621; Anticodon-bd_dom_sf. DR InterPro; IPR027031; Gly-tRNA_synthase/POLG2. DR InterPro; IPR042064; POLG2_C. DR PANTHER; PTHR10745:SF8; DNA POLYMERASE SUBUNIT GAMMA-2, MITOCHONDRIAL; 1. DR PANTHER; PTHR10745; GLYCYL-TRNA SYNTHETASE/DNA POLYMERASE SUBUNIT GAMMA-2; 1. DR Pfam; PF03129; HGTP_anticodon; 1. DR SUPFAM; SSF52954; Class II aaRS ABD-related; 1. DR SUPFAM; SSF55681; Class II aaRS and biotin synthetases; 1. PE 1: Evidence at protein level; KW 3D-structure; Disease variant; DNA replication; DNA-binding; Mitochondrion; KW Mitochondrion nucleoid; Phosphoprotein; Primary mitochondrial disease; KW Progressive external ophthalmoplegia; Proteomics identification; KW Reference proteome; Transit peptide. FT TRANSIT 1..? FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN ?..485 FT /note="DNA polymerase subunit gamma-2" FT /id="PRO_0000007314" FT REGION 28..65 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 46..58 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 38 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT VARIANT 169 FT /note="A -> T (in dbSNP:rs1427463)" FT /evidence="ECO:0000269|PubMed:10666468, FT ECO:0000269|PubMed:15489334" FT /id="VAR_032028" FT VARIANT 182 FT /note="R -> W (in MTDPS16; decreased function in FT mitochondrial DNA replication; decreased protein stability; FT no effect on DNA binding; dbSNP:rs886037843)" FT /evidence="ECO:0000269|PubMed:27592148, FT ECO:0000269|PubMed:30157269" FT /id="VAR_078773" FT VARIANT 416 FT /note="G -> A (no functional deficit; dbSNP:rs17850455)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:18195150" FT /id="VAR_032029" FT VARIANT 433 FT /note="D -> Y (in MTDPS16B; decreased DNA polymerase FT processivity factor activity; results in decreased FT stability; affects the secondary structure as shown by FT circular dichroism spectroscopy; dbSNP:rs2144120492)" FT /evidence="ECO:0000269|PubMed:31778857" FT /id="VAR_086017" FT VARIANT 451 FT /note="G -> E (in PEOA4; affects stimulation of the FT catalytic subunit; dbSNP:rs104894632)" FT /evidence="ECO:0000269|PubMed:16685652" FT /id="VAR_029364" FT CONFLICT 114..124 FT /note="WWTSVVVFREQ -> MVDLGGGVHGA (in Ref. 5; AAC51321)" FT /evidence="ECO:0000305" FT CONFLICT 122 FT /note="R -> T (in Ref. 3; AAD56542)" FT /evidence="ECO:0000305" FT CONFLICT 136 FT /note="G -> S (in Ref. 3; AAD56542 and 5; AAC51321)" FT /evidence="ECO:0000305" FT CONFLICT 287..292 FT /note="NKLYYN -> TNFTTI (in Ref. 5; AAC51321)" FT /evidence="ECO:0000305" FT HELIX 65..75 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 78..80 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 83..85 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 88..93 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 101..118 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 119..121 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 125..127 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 135..137 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 138..141 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 144..146 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 152..156 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 157..159 FT /evidence="ECO:0007829|PDB:2G4C" FT HELIX 165..169 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 170..176 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:8V5R" FT HELIX 186..190 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 193..196 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 197..200 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 206..218 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 224..226 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 230..243 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 245..247 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 248..266 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 270..272 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 273..279 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 281..284 FT /evidence="ECO:0007829|PDB:3IKL" FT STRAND 285..293 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 296..308 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 309..314 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 319..321 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 324..326 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 329..331 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 334..341 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 342..353 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 359..361 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 362..365 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 376..378 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 379..381 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 383..387 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 392..408 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 413..415 FT /evidence="ECO:0007829|PDB:8D33" FT HELIX 416..418 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 419..421 FT /evidence="ECO:0007829|PDB:3IKL" FT HELIX 425..434 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 438..443 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 445..450 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 452..457 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 458..460 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 463..467 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 468..470 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 471..482 FT /evidence="ECO:0007829|PDB:8UDL" SQ SEQUENCE 485 AA; 54911 MW; B99734BFEA249192 CRC64; MRSRVAVRAC HKVCRCLLSG FGGRVDAGQP ELLTERSSPK GGHVKSHAEL EGNGEHPEAP GSGEGSEALL EICQRRHFLS GSKQQLSRDS LLSGCHPGFG PLGVELRKNL AAEWWTSVVV FREQVFPVDA LHHKPGPLLP GDSAFRLVSA ETLREILQDK ELSKEQLVAF LENVLKTSGK LRENLLHGAL EHYVNCLDLV NKRLPYGLAQ IGVCFHPVFD TKQIRNGVKS IGEKTEASLV WFTPPRTSNQ WLDFWLRHRL QWWRKFAMSP SNFSSSDCQD EEGRKGNKLY YNFPWGKELI ETLWNLGDHE LLHMYPGNVS KLHGRDGRKN VVPCVLSVNG DLDRGMLAYL YDSFQLTENS FTRKKNLHRK VLKLHPCLAP IKVALDVGRG PTLELRQVCQ GLFNELLENG ISVWPGYLET MQSSLEQLYS KYDEMSILFT VLVTETTLEN GLIHLRSRDT TMKEMMHISK LKDFLIKYIS SAKNV // ID PEO1_HUMAN Reviewed; 684 AA. AC Q96RR1; B2CQL2; Q6MZX2; Q6PJP5; Q96RR0; DT 25-OCT-2005, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 193. DE RecName: Full=Twinkle mtDNA helicase {ECO:0000312|HGNC:HGNC:1160}; DE EC=5.6.2.3 {ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:27226550}; DE AltName: Full=Progressive external ophthalmoplegia 1 protein; DE AltName: Full=T7 gp4-like protein with intramitochondrial nucleoid localization; DE AltName: Full=T7-like mitochondrial DNA helicase; DE AltName: Full=Twinkle protein, mitochondrial {ECO:0000305}; DE Flags: Precursor; GN Name=TWNK {ECO:0000312|HGNC:HGNC:1160}; Synonyms=C10orf2, PEO1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, RP SUBCELLULAR LOCATION, VARIANT ILE-368, AND VARIANTS PEOA3 LEU-315; PRO-354; RP THR-359; THR-367; PRO-369; GLN-374; PRO-381; CYS-474 AND PRO-475. RX PubMed=11431692; DOI=10.1038/90058; RA Spelbrink J.N., Li F.-Y., Tiranti V., Nikali K., Yuan Q.-P., Tariq M., RA Wanrooij S., Garrido N., Comi G., Morandi L., Santoro L., Toscano A., RA Fabrizi G.-M., Somer H., Croxen R., Beeson D., Poulton J., Suomalainen A., RA Jacobs H.T., Zeviani M., Larsson C.; RT "Human mitochondrial DNA deletions associated with mutations in the gene RT for Twinkle, a phage T7 gene 4-like protein localized in mitochondria."; RL Nat. Genet. 28:223-231(2001). RN [2] RP ERRATUM OF PUBMED:11431692. RA Spelbrink J.N., Li F.-Y., Tiranti V., Nikali K., Yuan Q.-P., Tariq M., RA Wanrooij S., Garrido N., Comi G., Morandi L., Santoro L., Toscano A., RA Fabrizi G.-M., Somer H., Croxen R., Beeson D., Poulton J., Suomalainen A., RA Jacobs H.T., Zeviani M., Larsson C.; RL Nat. Genet. 29:100-100(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Fetal brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-348; ILE-368 AND RP LYS-634. RG NIEHS SNPs program; RL Submitted (MAR-2008) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 132-582 (ISOFORM 2). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP FUNCTION (ISOFORM 1), AND CATALYTIC ACTIVITY (ISOFORM 1). RX PubMed=12975372; DOI=10.1074/jbc.m306981200; RA Korhonen J.A., Gaspari M., Falkenberg M.; RT "TWINKLE has 5' -> 3' DNA helicase activity and is specifically stimulated RT by mitochondrial single-stranded DNA-binding protein."; RL J. Biol. Chem. 278:48627-48632(2003). RN [9] RP FUNCTION (ISOFORM 1), AND INTERACTION WITH POLG (ISOFORM 1). RX PubMed=15167897; DOI=10.1038/sj.emboj.7600257; RA Korhonen J.A., Pham X.H., Pellegrini M., Falkenberg M.; RT "Reconstitution of a minimal mtDNA replisome in vitro."; RL EMBO J. 23:2423-2429(2004). RN [10] RP TISSUE SPECIFICITY, AND COREGULATION WITH MRPL43. RX PubMed=15509589; DOI=10.1093/hmg/ddh342; RA Tyynismaa H., Sembongi H., Bokori-Brown M., Granycome C., Ashley N., RA Poulton J., Jalanko A., Spelbrink J.N., Holt I.J., Suomalainen A.; RT "Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA RT copy number."; RL Hum. Mol. Genet. 13:3219-3227(2004). RN [11] RP INTERACTION WITH LONP1. RX PubMed=14739292; DOI=10.1074/jbc.m309642200; RA Liu T., Lu B., Lee I., Ondrovicova G., Kutejova E., Suzuki C.K.; RT "DNA and RNA binding by the mitochondrial lon protease is regulated by RT nucleotide and protein substrate."; RL J. Biol. Chem. 279:13902-13910(2004). RN [12] RP POSSIBLE MECHANISM OF DELETION FORMATION. RX PubMed=15181170; DOI=10.1093/nar/gkh634; RA Wanrooij S., Luoma P., van Goethem G., van Broeckhoven C., Suomalainen A., RA Spelbrink J.N.; RT "Twinkle and POLG defects enhance age-dependent accumulation of mutations RT in the control region of mtDNA."; RL Nucleic Acids Res. 32:3053-3064(2004). RN [13] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), AND SUBUNIT (ISOFORM RP 1). RX PubMed=17324440; DOI=10.1016/j.jmb.2007.01.079; RA Ziebarth T.D., Farr C.L., Kaguni L.S.; RT "Modular architecture of the hexameric human mitochondrial DNA helicase."; RL J. Mol. Biol. 367:1382-1391(2007). RN [14] RP FUNCTION (ISOFORMS 1 AND 2), CATALYTIC ACTIVITY (ISOFORM 1), SUBUNIT RP (ISOFORMS 1 AND 2), AND DOMAIN. RX PubMed=18039713; DOI=10.1093/nar/gkm1025; RA Farge G., Holmlund T., Khvorostova J., Rofougaran R., Hofer A., RA Falkenberg M.; RT "The N-terminal domain of TWINKLE contributes to single-stranded DNA RT binding and DNA helicase activities."; RL Nucleic Acids Res. 36:393-403(2008). RN [15] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), SUBUNIT (ISOFORM 1), RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS LEU-315; GLU-319; RP THR-359; PRO-369; GLN-374 AND CYS-474. RX PubMed=18971204; DOI=10.1093/hmg/ddn359; RA Goffart S., Cooper H.M., Tyynismaa H., Wanrooij S., Suomalainen A., RA Spelbrink J.N.; RT "Twinkle mutations associated with autosomal dominant progressive external RT ophthalmoplegia lead to impaired helicase function and in vivo mtDNA RT replication stalling."; RL Hum. Mol. Genet. 18:328-340(2009). RN [16] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), ACTIVITY REGULATION RP (ISOFORM 1), BIOPHYSICOCHEMICAL PROPERTIES (ISOFORM 1), SUBUNIT (ISOFORM RP 1), AND MUTAGENESIS OF LYS-421. RX PubMed=22383523; DOI=10.1074/jbc.m111.309468; RA Sen D., Nandakumar D., Tang G.Q., Patel S.S.; RT "Human mitochondrial DNA helicase TWINKLE is both an unwinding and RT annealing helicase."; RL J. Biol. Chem. 287:14545-14556(2012). RN [17] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), AND SUBUNIT (ISOFORM RP 1). RX PubMed=25824949; DOI=10.1093/nar/gkv189; RA Fernandez-Millan P., Lazaro M., Cansiz-Arda S., Gerhold J.M., Rajala N., RA Schmitz C.A., Silva-Espina C., Gil D., Bernado P., Valle M., RA Spelbrink J.N., Sola M.; RT "The hexameric structure of the human mitochondrial replicative helicase RT Twinkle."; RL Nucleic Acids Res. 43:4284-4295(2015). RN [18] RP FUNCTION (ISOFORM 1). RX PubMed=26887820; DOI=10.1093/nar/gkw098; RA Sen D., Patel G., Patel S.S.; RT "Homologous DNA strand exchange activity of the human mitochondrial DNA RT helicase TWINKLE."; RL Nucleic Acids Res. 44:4200-4210(2016). RN [19] RP FUNCTION (ISOFORM 1), AND CATALYTIC ACTIVITY (ISOFORM 1). RX PubMed=27226550; DOI=10.1074/jbc.m115.712026; RA Khan I., Crouch J.D., Bharti S.K., Sommers J.A., Carney S.M., RA Yakubovskaya E., Garcia-Diaz M., Trakselis M.A., Brosh R.M. Jr.; RT "Biochemical Characterization of the Human Mitochondrial Replicative RT Twinkle Helicase: SUBSTRATE SPECIFICITY, DNA BRANCH MIGRATION, AND ABILITY RT TO OVERCOME BLOCKADES TO DNA UNWINDING."; RL J. Biol. Chem. 291:14324-14339(2016). RN [20] RP SUBUNIT (ISOFORM 1), AND CHARACTERIZATION OF PEOA3 LEU-314; GLN-334; RP LEU-335; PRO-369 AND PRO-381. RX PubMed=30496414; DOI=10.1093/hmg/ddy415; RA Peter B., Farge G., Pardo-Hernandez C., Taangefjord S., Falkenberg M.; RT "Structural basis for adPEO-causing mutations in the mitochondrial TWINKLE RT helicase."; RL Hum. Mol. Genet. 28:1090-1099(2019). RN [21] RP SUBCELLULAR LOCATION. RX PubMed=34950192; DOI=10.3389/fgene.2021.790521; RA So M., Stiban J., Ciesielski G.L., Hovde S.L., Kaguni L.S.; RT "Implications of Membrane Binding by the Fe-S Cluster-Containing N-Terminal RT Domain in the Drosophila Mitochondrial Replicative DNA Helicase."; RL Front. Genet. 12:790521-790521(2021). RN [22] {ECO:0007744|PDB:7T8B, ECO:0007744|PDB:7T8C} RP STRUCTURE BY ELECTRON MICROSCOPY (3.8 ANGSTROMS) OF 1-684 OF VARIANT RP LEU-315, CATALYTIC ACTIVITY, SUBUNIT, AND CHARACTERIZATION OF VARIANT RP LEU-315. RX PubMed=35914129; DOI=10.1073/pnas.2207459119; RA Riccio A.A., Bouvette J., Perera L., Longley M.J., Krahn J.M., RA Williams J.G., Dutcher R., Borgnia M.J., Copeland W.C.; RT "Structural insight and characterization of human Twinkle helicase in RT mitochondrial disease."; RL Proc. Natl. Acad. Sci. U.S.A. 119:e2207459119-e2207459119(2022). RN [23] RP VARIANTS PEOA3 LEU-335 AND TYR-369. RX PubMed=12163192; DOI=10.1016/s0022-510x(02)00190-9; RA Lewis S., Hutchison W., Thyagarajan D., Dahl H.-H.M.; RT "Clinical and molecular features of adPEO due to mutations in the Twinkle RT gene."; RL J. Neurol. Sci. 201:39-44(2002). RN [24] RP VARIANT ILE-368. RX PubMed=12557300; DOI=10.1002/ana.10430; RA Arenas J., Briem E., Dahl H.-H.M., Hutchison W., Lewis S., Martin M.A., RA Spelbrink H., Tiranti V., Jacobs H., Zeviani M.; RT "The V368I mutation in Twinkle does not segregate with AdPEO."; RL Ann. Neurol. 53:278-278(2003). RN [25] RP VARIANT PEO GLN-334. RX PubMed=12872260; DOI=10.1002/humu.10246; RA Van Goethem G., Loefgren A., Dermaut B., Ceuterick C., Martin J.-J., RA Van Broeckhoven C.; RT "Digenic progressive external ophthalmoplegia in a sporadic patient: RT recessive mutations in POLG and C10orf2/Twinkle."; RL Hum. Mutat. 22:175-176(2003). RN [26] RP VARIANTS PEO TRP-303 AND GLN-334. RX PubMed=12707443; DOI=10.1212/01.wnl.0000056088.09408.3c; RA Agostino A., Valletta L., Chinnery P.F., Ferrari G., Carrara F., RA Taylor R.W., Schaefer A.M., Turnbull D.M., Tiranti V., Zeviani M.; RT "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external RT ophthalmoplegia (PEO)."; RL Neurology 60:1354-1356(2003). RN [27] RP VARIANT PEOA3 THR-319. RX PubMed=12921794; DOI=10.1016/s0960-8966(03)00071-3; RA Deschauer M., Kiefer R., Blakely E.L., He L., Zierz S., Turnbull D.M., RA Taylor R.W.; RT "A novel Twinkle gene mutation in autosomal dominant progressive external RT ophthalmoplegia."; RL Neuromuscul. Disord. 13:568-572(2003). RN [28] RP VARIANT MTDPS7 CYS-508. RX PubMed=16135556; DOI=10.1093/hmg/ddi328; RA Nikali K., Suomalainen A., Saharinen J., Kuokkanen M., Spelbrink J.N., RA Loennqvist T., Peltonen L.; RT "Infantile onset spinocerebellar ataxia is caused by recessive mutations in RT mitochondrial proteins Twinkle and Twinky."; RL Hum. Mol. Genet. 14:2981-2990(2005). RN [29] RP VARIANT PEOA3 GLU-319. RX PubMed=15668446; DOI=10.1212/01.wnl.0000149767.51152.83; RA Hudson G., Deschauer M., Busse K., Zierz S., Chinnery P.F.; RT "Sensory ataxic neuropathy due to a novel C10Orf2 mutation with probable RT germline mosaicism."; RL Neurology 64:371-373(2005). RN [30] RP VARIANT PEOA3 GLN-374, AND VARIANT ILE-368. RX PubMed=16639411; DOI=10.1038/sj.ejhg.5201627; RA Naiemi M., Bannwarth S., Procaccio V., Pouget J., Desnuelle C., RA Pellissier J.-F., Roetig A., Munnich A., Calvas P., Richelme C., RA Jonveaux P., Castelnovo G., Simon M., Clanet M., Wallace D., RA Paquis-Flucklinger V.; RT "Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple RT deletions or depletion of mitochondrial DNA by a dHPLC-based assay."; RL Eur. J. Hum. Genet. 14:917-922(2006). RN [31] RP VARIANT MTDPS7 ILE-457, AND CHARACTERIZATION OF VARIANT MTDPS7 ILE-457. RX PubMed=17722119; DOI=10.1002/ana.21207; RA Sarzi E., Goffart S., Serre V., Chretien D., Slama A., Munnich A., RA Spelbrink J.N., Roetig A.; RT "Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA RT depletion."; RL Ann. Neurol. 62:579-587(2007). RN [32] RP VARIANTS MTDPS7 THR-318 AND CYS-508. RX PubMed=17921179; DOI=10.1093/brain/awm242; RA Hakonen A.H., Isohanni P., Paetau A., Herva R., Suomalainen A., RA Lonnqvist T.; RT "Recessive Twinkle mutations in early onset encephalopathy with mtDNA RT depletion."; RL Brain 130:3032-3040(2007). RN [33] RP VARIANT PEOA3 PRO-357. RX PubMed=17614277; DOI=10.1016/j.nmd.2007.05.006; RA Rivera H., Blazquez A., Carretero J., Alvarez-Cermeno J.C., Campos Y., RA Cabello A., Gonzalez-Vioque E., Borstein B., Garesse R., Arenas J., RA Martin M.A.; RT "Mild ocular myopathy associated with a novel mutation in mitochondrial RT twinkle helicase."; RL Neuromuscul. Disord. 17:677-680(2007). RN [34] RP VARIANTS PEOA3 TRP-303; SER-315; PRO-334; ASN-426; SER-474; ILE-478 AND RP LYS-479. RX PubMed=18575922; DOI=10.1007/s00415-008-0926-3; RA Virgilio R., Ronchi D., Hadjigeorgiou G.M., Bordoni A., Saladino F., RA Moggio M., Adobbati L., Kafetsouli D., Tsironi E., Previtali S., RA Papadimitriou A., Bresolin N., Comi G.P.; RT "Novel Twinkle (PEO1) gene mutations in Mendelian progressive external RT ophthalmoplegia."; RL J. Neurol. 255:1384-1391(2008). RN [35] RP VARIANT PEOA3 LEU-370. RX PubMed=18396044; DOI=10.1016/j.nmd.2007.10.007; RA Jeppesen T.D., Schwartz M., Colding-Jorgensen E., Krag T., Hauerslev S., RA Vissing J.; RT "Phenotype and clinical course in a family with a new de novo Twinkle gene RT mutation."; RL Neuromuscul. Disord. 18:306-309(2008). RN [36] RP VARIANT PEOA3 GLN-303. RX PubMed=19353676; DOI=10.1002/ajmg.a.32731; RA Van Hove J.L., Cunningham V., Rice C., Ringel S.P., Zhang Q., Chou P.C., RA Truong C.K., Wong L.J.; RT "Finding twinkle in the eyes of a 71-year-old lady: a case report and RT review of the genotypic and phenotypic spectrum of TWINKLE-related dominant RT disease."; RL Am. J. Med. Genet. A 149:861-867(2009). RN [37] RP VARIANT PEOA3 TRP-303. RX PubMed=19428252; DOI=10.1016/j.nmd.2009.04.008; RA Negro R., Zoccolella S., Dell'aglio R., Amati A., Artuso L., Bisceglia L., RA Lavolpe V., Papa S., Serlenga L., Petruzzella V.; RT "Molecular analysis in a family presenting with a mild form of late-onset RT autosomal dominant chronic progressive external ophthalmoplegia."; RL Neuromuscul. Disord. 19:423-426(2009). RN [38] RP VARIANT MTDPS7 GLY-360. RX PubMed=19853444; DOI=10.1016/j.nmd.2009.10.002; RA Bohlega S., Van Goethem G., Al Semari A., Lofgren A., Al Hamed M., RA Van Broeckhoven C., Kambouris M.; RT "Novel Twinkle gene mutation in autosomal dominant progressive external RT ophthalmoplegia and multisystem failure."; RL Neuromuscul. Disord. 19:845-848(2009). RN [39] RP VARIANTS PEOA3 GLN-303; TRP-303; GLN-334; PRO-354; PRO-357; THR-359; RP PRO-362; LEU-363; CYS-370; GLN-374; PRO-381; HIS-458; PRO-460; ASP-475 AND RP LYS-479. RX PubMed=20479361; DOI=10.1212/wnl.0b013e3181df099f; RA Fratter C., Gorman G.S., Stewart J.D., Buddles M., Smith C., Evans J., RA Seller A., Poulton J., Roberts M., Hanna M.G., Rahman S., Omer S.E., RA Klopstock T., Schoser B., Kornblum C., Czermin B., Lecky B., Blakely E.L., RA Craig K., Chinnery P.F., Turnbull D.M., Horvath R., Taylor R.W.; RT "The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)- RT linked adPEO."; RL Neurology 74:1619-1626(2010). RN [40] RP VARIANT PEOA3 GLN-374. RX PubMed=20880070; DOI=10.1111/j.1468-1331.2010.03171.x; RA Martin-Negrier M.L., Sole G., Jardel C., Vital C., Ferrer X., Vital A.; RT "TWINKLE gene mutation: report of a French family with an autosomal RT dominant progressive external ophthalmoplegia and literature review."; RL Eur. J. Neurol. 18:436-441(2011). RN [41] RP VARIANT MTDPS7 VAL-456. RX PubMed=22353293; DOI=10.1016/j.pediatrneurol.2011.12.006; RA Dundar H., Ozgul R.K., Yalnizoglu D., Erdem S., Oguz K.K., Tuncel D., RA Temucin C.M., Dursun A.; RT "Identification of a novel Twinkle mutation in a family with infantile RT onset spinocerebellar ataxia by whole exome sequencing."; RL Pediatr. Neurol. 46:172-177(2012). RN [42] RP INVOLVEMENT IN PRLTS5, AND VARIANTS PRLTS5 HIS-391; GLY-441; ILE-507 AND RP SER-585. RX PubMed=25355836; DOI=10.1212/wnl.0000000000001036; RA Morino H., Pierce S.B., Matsuda Y., Walsh T., Ohsawa R., Newby M., RA Hiraki-Kamon K., Kuramochi M., Lee M.K., Klevit R.E., Martin A., RA Maruyama H., King M.C., Kawakami H.; RT "Mutations in Twinkle primase-helicase cause Perrault syndrome with RT neurologic features."; RL Neurology 83:2054-2061(2014). CC -!- FUNCTION: [Isoform 1]: Mitochondrial helicase involved in mtDNA CC replication and repair (PubMed:12975372, PubMed:15167897, CC PubMed:17324440, PubMed:18039713, PubMed:18971204, PubMed:25824949, CC PubMed:26887820, PubMed:27226550). Might have a role in mtDNA repair CC (PubMed:27226550). Has DNA strand separation activity needed to form a CC processive replication fork for leading strand synthesis which is CC catalyzed by the formation of a replisome complex with POLG and mtSDB CC (PubMed:12975372, PubMed:15167897, PubMed:18039713, PubMed:22383523, CC PubMed:26887820, PubMed:27226550). Preferentially unwinds DNA CC substrates with pre-existing 5'-and 3'- single-stranded tails but is CC also active on a 5'- flap substrate (PubMed:12975372, PubMed:15167897, CC PubMed:18039713, PubMed:22383523, PubMed:26887820, PubMed:27226550). CC Can dissociate the invading strand of immobile or mobile D-loop DNA CC structures irrespective of the single strand polarity of the third CC strand (PubMed:27226550). In addition to its DNA strand separation CC activity, also has DNA strand annealing, DNA strand-exchange and DNA CC branch migration activities (PubMed:22383523, PubMed:26887820, CC PubMed:27226550). {ECO:0000269|PubMed:12975372, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:17324440, CC ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204, CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949, CC ECO:0000269|PubMed:26887820, ECO:0000269|PubMed:27226550}. CC -!- FUNCTION: [Isoform 2]: Lack DNA unwinding and ATP hydrolysis activities CC (PubMed:18039713). Does not bind single-stranded or double-stranded DNA CC (PubMed:18039713). {ECO:0000269|PubMed:18039713}. CC -!- CATALYTIC ACTIVITY: [Isoform 1]: CC Reaction=ATP + H2O = ADP + phosphate + H(+); Xref=Rhea:RHEA:13065, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=5.6.2.3; CC Evidence={ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:17324440, CC ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204, CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949, CC ECO:0000269|PubMed:27226550, ECO:0000269|PubMed:35914129}; CC -!- CATALYTIC ACTIVITY: [Isoform 1]: CC Reaction=Couples ATP hydrolysis with the unwinding of duplex DNA at the CC replication fork by translocating in the 5'-3' direction.; CC EC=5.6.2.3; Evidence={ECO:0000269|PubMed:12975372, CC ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713, CC ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523, CC ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:27226550, CC ECO:0000269|PubMed:35914129}; CC -!- ACTIVITY REGULATION: [Isoform 1]: Strand annealing activity is CC inhibited by 150 mM NaCl (in vitro). {ECO:0000269|PubMed:22383523}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform 1]: CC Kinetic parameters: CC KM=1.7 mM for UTP (using ssM13mp18 as DNA substrate) CC {ECO:0000269|PubMed:22383523}; CC KM=1.6 mM for UTP (using ssDNA as DNA substrate) CC {ECO:0000269|PubMed:22383523}; CC KM=1.4 mM for UTP (using forked dsDNA as DNA substrate) CC {ECO:0000269|PubMed:22383523}; CC KM=3.4 mM for UTP (using no DNA as substrate) CC {ECO:0000269|PubMed:22383523}; CC -!- SUBUNIT: Interacts with LONP1. {ECO:0000269|PubMed:14739292}. CC -!- SUBUNIT: [Isoform 1]: Homohexamer (via C-terminus), which assembles in CC a ring-like structure (PubMed:17324440, PubMed:18039713, CC PubMed:18971204, PubMed:22383523, PubMed:25824949, PubMed:30496414). CC Homoheptamer, which assembles in a ring-like structure CC (PubMed:25824949, PubMed:30496414, PubMed:35914129). Homooctamer, which CC assembles in a ring-like structure (PubMed:35914129). Oligomers may CC sequentially eject two monomers (octamer>heptamer>hexamer) upon DNA CC binding (PubMed:35914129). Oligomerization is Mg(2+), nucleotide and CC DNA-independent, however, Mg(2+) and nucleotide stabilize the CC homohexameric form (PubMed:18039713). Interacts with POLG in vitro CC (PubMed:15167897). {ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713, CC ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523, CC ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:30496414, CC ECO:0000269|PubMed:35914129}. CC -!- SUBUNIT: [Isoform 2]: Monomer (PubMed:18039713). Does not form CC oligomers (PubMed:18039713). {ECO:0000269|PubMed:18039713}. CC -!- INTERACTION: CC Q96RR1; Q08380: LGALS3BP; NbExp=2; IntAct=EBI-716458, EBI-354956; CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix, mitochondrion nucleoid CC {ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:18971204}. CC Mitochondrion inner membrane {ECO:0000303|PubMed:34950192}; Peripheral CC membrane protein {ECO:0000269|PubMed:34950192}. Note=Colocalizes with CC mtDNA in mitochondrial nucleoids, a nucleoproteins complex consisting CC of a number of copies of proteins associated with mtDNA, probably CC involved in mtDNA maintenance and expression (PubMed:11431692). CC Associates with phospholipid membranes via electrostatic binding (By CC similarity). Preferentially associates with membranes enriched with CC cardiolipin, a lipid abundant in the mitochondrial inner membrane CC (PubMed:34950192). ATPase and helicase activity is enhanced by binding CC to lipid membranes (PubMed:34950192). {ECO:0000250|UniProtKB:Q9VL76, CC ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:34950192}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q96RR1-1; Sequence=Displayed; CC Name=2; Synonyms=Twinky; CC IsoId=Q96RR1-2; Sequence=VSP_015960, VSP_015961; CC Name=3; CC IsoId=Q96RR1-3; Sequence=VSP_015959; CC -!- TISSUE SPECIFICITY: High relative levels in skeletal muscle, testis and CC pancreas. Lower levels of expression in the heart, brain, placenta, CC lung, liver, kidney, spleen, thymus, prostate, ovary, small intestine, CC colon and leukocytes. Expression is coregulated with MRPL43. CC {ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:15509589}. CC -!- DOMAIN: N-terminus enhances protein stability and hexamer formation, CC which is important for DNA binding, and is required for DNA helicase CC activity and, ultimately, for mtDNA replisome processivity. CC {ECO:0000269|PubMed:18039713}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 3 (PEOA3) [MIM:609286]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:11431692, CC ECO:0000269|PubMed:12163192, ECO:0000269|PubMed:12921794, CC ECO:0000269|PubMed:15668446, ECO:0000269|PubMed:16639411, CC ECO:0000269|PubMed:17614277, ECO:0000269|PubMed:18396044, CC ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:19353676, CC ECO:0000269|PubMed:19428252, ECO:0000269|PubMed:20479361, CC ECO:0000269|PubMed:20880070}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 7 (MTDPS7) [MIM:271245]: CC A severe disease associated with mitochondrial dysfunction. Some CC patients are affected by progressive atrophy of the cerebellum, brain CC stem, the spinal cord, and sensory axonal neuropathy. Clinical features CC include hypotonia, athetosis, ataxia, ophthalmoplegia, sensorineural CC hearing deficit, sensory axonal neuropathy, epileptic encephalopathy CC and female hypogonadism. In some individuals liver dysfunction and CC multi-organ failure is present. {ECO:0000269|PubMed:16135556, CC ECO:0000269|PubMed:17722119, ECO:0000269|PubMed:17921179, CC ECO:0000269|PubMed:19853444, ECO:0000269|PubMed:22353293}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Perrault syndrome 5 (PRLTS5) [MIM:616138]: A form of Perrault CC syndrome, a sex-influenced disorder characterized by sensorineural CC deafness in both males and females, and ovarian dysgenesis in females. CC Affected females have primary amenorrhea, streak gonads, and CC infertility, whereas affected males show normal pubertal development CC and are fertile. PRLTS5 is an autosomal recessive form characterized by CC progressive ataxia, axonal neuropathy, hyporeflexia and abnormal eye CC movements, in addition to deafness and ovarian dysgenesis. CC {ECO:0000269|PubMed:25355836}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- CAUTION: The N-terminus contains a putative primase-like domain; CC however the absence of the zinc binding domain and other motifs CC important for catalysis suggests that TWNK lacks primase activity. CC {ECO:0000305|PubMed:25824949}. CC -!- CAUTION: In vitro, can catalyze the hydrolysis of different nucleotide CC triphosphate (NTP) substrates with different efficiency. CC {ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:18971204, CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF292004; AAK69558.1; -; mRNA. DR EMBL; AF292005; AAK69559.1; -; mRNA. DR EMBL; BX640829; CAE45905.1; -; mRNA. DR EMBL; AL133215; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; EU543650; ACB21043.1; -; Genomic_DNA. DR EMBL; CH471066; EAW49794.1; -; Genomic_DNA. DR EMBL; BC013349; AAH13349.1; -; mRNA. DR CCDS; CCDS53570.1; -. [Q96RR1-2] DR CCDS; CCDS7506.1; -. [Q96RR1-1] DR RefSeq; NP_001157284.1; NM_001163812.2. [Q96RR1-2] DR RefSeq; NP_068602.2; NM_021830.4. [Q96RR1-1] DR PDB; 7T8B; EM; 3.80 A; A/B/C/D/E/F/G/H=1-684. DR PDB; 7T8C; EM; 4.50 A; A/B/C/D/E/F/G=1-684. DR PDBsum; 7T8B; -. DR PDBsum; 7T8C; -. DR AlphaFoldDB; Q96RR1; -. DR EMDB; EMD-25743; -. DR EMDB; EMD-25744; -. DR SMR; Q96RR1; -. DR BioGRID; 121166; 148. DR FunCoup; Q96RR1; 1571. DR IntAct; Q96RR1; 83. DR MINT; Q96RR1; -. DR STRING; 9606.ENSP00000309595; -. DR GlyGen; Q96RR1; 1 site. DR iPTMnet; Q96RR1; -. DR PhosphoSitePlus; Q96RR1; -. DR BioMuta; TWNK; -. DR DMDM; 74752111; -. DR jPOST; Q96RR1; -. DR MassIVE; Q96RR1; -. DR PaxDb; 9606-ENSP00000309595; -. DR PeptideAtlas; Q96RR1; -. DR ProteomicsDB; 78006; -. [Q96RR1-1] DR ProteomicsDB; 78007; -. [Q96RR1-2] DR ProteomicsDB; 78008; -. [Q96RR1-3] DR Pumba; Q96RR1; -. DR Antibodypedia; 1261; 217 antibodies from 25 providers. DR DNASU; 56652; -. DR Ensembl; ENST00000311916.8; ENSP00000309595.2; ENSG00000107815.10. [Q96RR1-1] DR Ensembl; ENST00000370228.2; ENSP00000359248.1; ENSG00000107815.10. [Q96RR1-2] DR Ensembl; ENST00000643860.1; ENSP00000494389.1; ENSG00000107815.10. [Q96RR1-3] DR GeneID; 56652; -. DR KEGG; hsa:56652; -. DR MANE-Select; ENST00000311916.8; ENSP00000309595.2; NM_021830.5; NP_068602.2. DR UCSC; uc001ksf.3; human. [Q96RR1-1] DR AGR; HGNC:1160; -. DR ClinPGx; PA162377675; -. DR CTD; 56652; -. DR DisGeNET; 56652; -. DR GeneCards; TWNK; -. DR HGNC; HGNC:1160; TWNK. DR HPA; ENSG00000107815; Low tissue specificity. DR MalaCards; TWNK; -. DR MIM; 271245; phenotype. DR MIM; 606075; gene. DR MIM; 609286; phenotype. DR MIM; 616138; phenotype. DR OpenTargets; ENSG00000107815; -. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 1186; Infantile-onset spinocerebellar ataxia. DR Orphanet; 363534; Mitochondrial DNA depletion syndrome, hepatocerebrorenal form. DR Orphanet; 642945; Perrault syndrome type 1. DR Orphanet; 642976; Perrault syndrome type 2. DR Orphanet; 70595; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome. DR VEuPathDB; HostDB:ENSG00000107815; -. DR eggNOG; KOG2373; Eukaryota. DR GeneTree; ENSGT00390000004495; -. DR HOGENOM; CLU_012336_1_0_1; -. DR InParanoid; Q96RR1; -. DR OMA; GIRWSRF; -. DR OrthoDB; 275278at2759; -. DR PAN-GO; Q96RR1; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q96RR1; -. DR BRENDA; 3.6.4.12; 2681. DR PathwayCommons; Q96RR1; -. DR Reactome; R-HSA-2151201; Transcriptional activation of mitochondrial biogenesis. DR Reactome; R-HSA-9837999; Mitochondrial protein degradation. DR Reactome; R-HSA-9913635; Strand-asynchronous mitochondrial DNA replication. DR SignaLink; Q96RR1; -. DR Agora; ENSG00000107815; -. DR BioGRID-ORCS; 56652; 354 hits in 1149 CRISPR screens. DR ChiTaRS; TWNK; human. DR GeneWiki; PEO1; -. DR GenomeRNAi; 56652; -. DR Pharos; Q96RR1; Tbio. DR PRO; PR:Q96RR1; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; Q96RR1; protein. DR Bgee; ENSG00000107815; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 139 other cell types or tissues. DR ExpressionAtlas; Q96RR1; baseline and differential. DR GO; GO:0000262; C:mitochondrial chromosome; IDA:FlyBase. DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome. DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; HTP:FlyBase. DR GO; GO:0043139; F:5'-3' DNA helicase activity; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016887; F:ATP hydrolysis activity; IDA:FlyBase. DR GO; GO:0003678; F:DNA helicase activity; IBA:GO_Central. DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB. DR GO; GO:0008289; F:lipid binding; IDA:FlyBase. DR GO; GO:0002020; F:protease binding; IPI:UniProtKB. DR GO; GO:0003697; F:single-stranded DNA binding; IDA:UniProtKB. DR GO; GO:0006261; P:DNA-templated DNA replication; IDA:FlyBase. DR GO; GO:0006264; P:mitochondrial DNA replication; IMP:UniProtKB. DR GO; GO:0006390; P:mitochondrial transcription; IMP:UniProtKB. DR GO; GO:0034214; P:protein hexamerization; IDA:UniProtKB. DR CDD; cd01029; TOPRIM_primases; 1. DR CDD; cd01122; Twinkle_C; 1. DR FunFam; 3.40.1360.10:FF:000008; Mitochondrial helicase twinkle; 1. DR FunFam; 3.40.50.300:FF:000845; Mitochondrial helicase twinkle; 1. DR Gene3D; 3.40.1360.10; -; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR InterPro; IPR007694; DNA_helicase_DnaB-like_C. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR034154; TOPRIM_DnaG/twinkle. DR InterPro; IPR027032; Twinkle-like. DR PANTHER; PTHR12873; T7-LIKE MITOCHONDRIAL DNA HELICASE; 1. DR PANTHER; PTHR12873:SF0; TWINKLE MTDNA HELICASE; 1. DR Pfam; PF13481; AAA_25; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS51199; SF4_HELICASE; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Deafness; Disease variant; KW DNA replication; Helicase; Hydrolase; Isomerase; Lipid-binding; Membrane; KW Mitochondrion; Mitochondrion inner membrane; Mitochondrion nucleoid; KW Neurodegeneration; Neuropathy; Nucleotide-binding; KW Primary mitochondrial disease; Progressive external ophthalmoplegia; KW Proteomics identification; Reference proteome; Transit peptide. FT TRANSIT 1..31 FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN 32..684 FT /note="Twinkle mtDNA helicase" FT /id="PRO_0000042640" FT DOMAIN 384..635 FT /note="SF4 helicase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00596" FT REGION 1..121 FT /note="Contributes to single strand DNA binding activity" FT /evidence="ECO:0000269|PubMed:18039713" FT REGION 54..214 FT /note="N-terminal region (NTR)" FT /evidence="ECO:0000269|PubMed:35914129" FT REGION 121..372 FT /note="Required for hexamers formation and DNA helicase FT activity" FT /evidence="ECO:0000269|PubMed:18039713" FT REGION 215..335 FT /note="Primase-like domain" FT /evidence="ECO:0000269|PubMed:35914129" FT REGION 405..590 FT /note="Maybe required for stable oligomeric structure" FT /evidence="ECO:0000269|PubMed:17324440" FT REGION 637..684 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 640..684 FT /note="Might negatively regulate ATPase activity" FT /evidence="ECO:0000269|PubMed:17324440" FT COMPBIAS 659..677 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 415..422 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00596" FT VAR_SEQ 532..684 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_015959" FT VAR_SEQ 579..582 FT /note="ASQE -> VSGL (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11431692, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015960" FT VAR_SEQ 583..684 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11431692, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015961" FT VARIANT 303 FT /note="R -> Q (in PEOA3; dbSNP:rs137852956)" FT /evidence="ECO:0000269|PubMed:19353676, FT ECO:0000269|PubMed:20479361" FT /id="VAR_065102" FT VARIANT 303 FT /note="R -> W (in PEOA3; also detected in a case showing FT digenic inheritance; dbSNP:rs1159929268)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:19428252, FT ECO:0000269|PubMed:20479361" FT /id="VAR_023647" FT VARIANT 315 FT /note="W -> L (in PEOA3; reduced single-strand DNA binding; FT increased heptamer oligomerization; increased stability of FT the closed or 'compacted' conformation; dbSNP:rs111033575)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:30496414, ECO:0000269|PubMed:35914129" FT /id="VAR_023648" FT VARIANT 315 FT /note="W -> S (in PEOA3; reduces helicase activity; reduced FT single-strand DNA binding)" FT /evidence="ECO:0000269|PubMed:18575922, FT ECO:0000269|PubMed:18971204" FT /id="VAR_065103" FT VARIANT 318 FT /note="A -> T (in MTDPS7; dbSNP:rs80356542)" FT /evidence="ECO:0000269|PubMed:17921179" FT /id="VAR_065104" FT VARIANT 319 FT /note="K -> E (in PEOA3; the phenotype highly overlaps with FT sensory ataxic neuropathy dysarthria and ophthalmoparesis; FT reduces helicase activity and single-strand DNA binding; FT dbSNP:rs80356543)" FT /evidence="ECO:0000269|PubMed:15668446, FT ECO:0000269|PubMed:18971204" FT /id="VAR_023649" FT VARIANT 319 FT /note="K -> T (in PEOA3)" FT /evidence="ECO:0000269|PubMed:12921794" FT /id="VAR_023650" FT VARIANT 334 FT /note="R -> P (in PEOA3)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065105" FT VARIANT 334 FT /note="R -> Q (in PEO; sporadic case; the patient also FT carries the S-848 mutation in the POLG gene suggesting FT digenic inheritance; retains hexamer and heptamer FT formation; dbSNP:rs28937887)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:12872260, ECO:0000269|PubMed:20479361, FT ECO:0000269|PubMed:30496414" FT /id="VAR_023651" FT VARIANT 335 FT /note="P -> L (in PEOA3; displays unusual oligomeric FT forms)" FT /evidence="ECO:0000269|PubMed:12163192, FT ECO:0000269|PubMed:30496414" FT /id="VAR_023652" FT VARIANT 348 FT /note="G -> R (in dbSNP:rs62626271)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_062268" FT VARIANT 354 FT /note="R -> P (in PEOA3; dbSNP:rs111033576)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:20479361" FT /id="VAR_023653" FT VARIANT 357 FT /note="R -> P (in PEOA3; dbSNP:rs758026634)" FT /evidence="ECO:0000269|PubMed:17614277, FT ECO:0000269|PubMed:20479361" FT /id="VAR_065106" FT VARIANT 359 FT /note="A -> T (in PEOA3; reduces helicase activity; FT dbSNP:rs111033573)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:20479361" FT /id="VAR_023654" FT VARIANT 360 FT /note="L -> G (in MTDPS7; patients manifest multi-organ FT failure; requires 2 nucleotide substitutions)" FT /evidence="ECO:0000269|PubMed:19853444" FT /id="VAR_065107" FT VARIANT 362 FT /note="A -> P (in PEOA3; dbSNP:rs1554887075)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065108" FT VARIANT 363 FT /note="W -> L (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065109" FT VARIANT 367 FT /note="I -> T (in PEOA3)" FT /evidence="ECO:0000269|PubMed:11431692" FT /id="VAR_023655" FT VARIANT 368 FT /note="V -> I (in dbSNP:rs17113613)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:12557300, ECO:0000269|PubMed:16639411, FT ECO:0000269|Ref.4" FT /id="VAR_023656" FT VARIANT 369 FT /note="S -> P (in PEOA3; reduces helicase activity; FT increases single strand DNA affinity; reduces closed-ring FT quaternary structure formation)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:30496414" FT /id="VAR_023657" FT VARIANT 369 FT /note="S -> Y (in PEOA3; dbSNP:rs111033579)" FT /evidence="ECO:0000269|PubMed:12163192" FT /id="VAR_023658" FT VARIANT 370 FT /note="F -> C (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065110" FT VARIANT 370 FT /note="F -> L (in PEOA3; dbSNP:rs863223920)" FT /evidence="ECO:0000269|PubMed:18396044" FT /id="VAR_065111" FT VARIANT 374 FT /note="R -> Q (in PEOA3; reduces helicase activity and FT alters nucleoid structure; dbSNP:rs1554887097)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18971204, FT ECO:0000269|PubMed:20479361, ECO:0000269|PubMed:20880070" FT /id="VAR_023659" FT VARIANT 381 FT /note="L -> P (in PEOA3; reduces closed-ring quaternary FT structure formation; dbSNP:rs111033577)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:20479361, ECO:0000269|PubMed:30496414" FT /id="VAR_023660" FT VARIANT 391 FT /note="R -> H (in PRLTS5; dbSNP:rs556445621)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072657" FT VARIANT 426 FT /note="S -> N (in PEOA3)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065112" FT VARIANT 427 FT /note="E -> G (in dbSNP:rs11542126)" FT /id="VAR_051267" FT VARIANT 441 FT /note="W -> G (in PRLTS5; dbSNP:rs672601361)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072658" FT VARIANT 456 FT /note="L -> V (in MTDPS7; infantile spinocerebellar ataxia FT phenotype; dbSNP:rs386834145)" FT /evidence="ECO:0000269|PubMed:22353293" FT /id="VAR_067722" FT VARIANT 457 FT /note="T -> I (in MTDPS7; affects helicase activity; FT dbSNP:rs80356544)" FT /evidence="ECO:0000269|PubMed:17722119" FT /id="VAR_039045" FT VARIANT 458 FT /note="Q -> H (in PEOA3; dbSNP:rs1554887213)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065113" FT VARIANT 460 FT /note="A -> P (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065114" FT VARIANT 474 FT /note="W -> C (in PEOA3; reduces helicase activity and FT alters nucleoid structure; dbSNP:rs111033574)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:18971204" FT /id="VAR_023661" FT VARIANT 474 FT /note="W -> S (in PEOA3; dbSNP:rs11542127)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065115" FT VARIANT 475 FT /note="A -> D (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065116" FT VARIANT 475 FT /note="A -> P (in PEOA3; dbSNP:rs111033572)" FT /evidence="ECO:0000269|PubMed:11431692" FT /id="VAR_023662" FT VARIANT 478 FT /note="F -> I (in PEOA3)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065117" FT VARIANT 479 FT /note="E -> K (in PEOA3; dbSNP:rs1085307937)" FT /evidence="ECO:0000269|PubMed:18575922, FT ECO:0000269|PubMed:20479361" FT /id="VAR_065118" FT VARIANT 507 FT /note="V -> I (in PRLTS5; dbSNP:rs369588002)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072659" FT VARIANT 508 FT /note="Y -> C (in MTDPS7; dbSNP:rs80356540)" FT /evidence="ECO:0000269|PubMed:16135556, FT ECO:0000269|PubMed:17921179" FT /id="VAR_043797" FT VARIANT 585 FT /note="N -> S (in PRLTS5; dbSNP:rs672601360)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072660" FT VARIANT 634 FT /note="N -> K (in dbSNP:rs62626293)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_062269" FT MUTAGEN 421 FT /note="K->A: Loss of helicase activity on 5'-tailed FT substrate." FT /evidence="ECO:0000269|PubMed:22383523" FT CONFLICT 351 FT /note="N -> D (in Ref. 3; CAE45905)" FT /evidence="ECO:0000305" SQ SEQUENCE 684 AA; 77154 MW; 58186043888234DA CRC64; MWVLLRSGYP LRILLPLRGE WMGRRGLPRN LAPGPPRRRY RKETLQALDM PVLPVTATEI RQYLRGHGIP FQDGHSCLRA LSPFAESSQL KGQTGVTTSF SLFIDKTTGH FLCMTSLAEG SWEDFQASVE GRGDGAREGF LLSKAPEFED SEEVRRIWNR AIPLWELPDQ EEVQLADTMF GLTKVTDDTL KRFSVRYLRP ARSLVFPWFS PGGSGLRGLK LLEAKCQGDG VSYEETTIPR PSAYHNLFGL PLISRRDAEV VLTSRELDSL ALNQSTGLPT LTLPRGTTCL PPALLPYLEQ FRRIVFWLGD DLRSWEAAKL FARKLNPKRC FLVRPGDQQP RPLEALNGGF NLSRILRTAL PAWHKSIVSF RQLREEVLGE LSNVEQAAGL RWSRFPDLNR ILKGHRKGEL TVFTGPTGSG KTTFISEYAL DLCSQGVNTL WGSFEISNVR LARVMLTQFA EGRLEDQLDK YDHWADRFED LPLYFMTFHG QQSIRTVIDT MQHAVYVYDI CHVIIDNLQF MMGHEQLSTD RIAAQDYIIG VFRKFATDNN CHVTLVIHPR KEDDDKELQT ASIFGSAKAS QEADNVLILQ DRKLVTGPGK RYLQVSKNRF DGDVGVFPLE FNKNSLTFSI PPKNKARLKK IKDDTGPVAK KPSSGKKGAT TQNSEICSGQ APTPDQPDTS KRSK // ID RIR2B_HUMAN Reviewed; 351 AA. AC Q7LG56; B4E2N4; Q17R22; Q75PQ6; Q75PQ7; Q75PY8; Q75PY9; Q86YE3; Q9NPD6; AC Q9NTD8; Q9NUW3; DT 21-MAR-2006, integrated into UniProtKB/Swiss-Prot. DT 05-JUL-2004, sequence version 1. DT 28-JAN-2026, entry version 197. DE RecName: Full=Ribonucleoside-diphosphate reductase subunit M2 B; DE EC=1.17.4.1; DE AltName: Full=TP53-inducible ribonucleotide reductase M2 B; DE AltName: Full=p53-inducible ribonucleotide reductase small subunit 2-like protein; DE Short=p53R2; GN Name=RRM2B; Synonyms=P53R2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), FUNCTION, AND RP INDUCTION. RX PubMed=10716435; DOI=10.1038/35003506; RA Tanaka H., Arakawa H., Yamaguchi T., Shiraishi K., Fukuda S., Matsui K., RA Takei Y., Nakamura Y.; RT "A ribonucleotide reductase gene involved in a p53-dependent cell-cycle RT checkpoint for DNA damage."; RL Nature 404:42-49(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4 AND 5). RA Ugai H., Yokoyama K.K.; RT "Homo sapiens p53-inducible ribonucleotide reductase small subunit 2 RT splicing variants."; RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE SEQUENCE RP [LARGE SCALE MRNA] OF 1-351 (ISOFORM 6). RC TISSUE=Placenta, and Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Amygdala; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16421571; DOI=10.1038/nature04406; RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., RA Platzer M., Shimizu N., Lander E.S.; RT "DNA sequence and analysis of human chromosome 8."; RL Nature 439:331-335(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain, and Eye; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP FUNCTION, AND SUBUNIT. RX PubMed=11517226; DOI=10.1074/jbc.m106088200; RA Guittet O., Haakansson P., Voevodskaya N., Fridd S., Graeslund A., RA Arakawa H., Nakamura Y., Thelander L.; RT "Mammalian p53R2 protein forms an active ribonucleotide reductase in vitro RT with the R1 protein, which is expressed both in resting cells in response RT to DNA damage and in proliferating cells."; RL J. Biol. Chem. 276:40647-40651(2001). RN [10] RP FUNCTION, SUBCELLULAR LOCATION, AND VARIANT LEU-115. RX PubMed=11719458; RA Yamaguchi T., Matsuda K., Sagiya Y., Iwadate M., Fujino M.A., Nakamura Y., RA Arakawa H.; RT "p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle RT checkpoint."; RL Cancer Res. 61:8256-8262(2001). RN [11] RP SUBCELLULAR LOCATION, AND INTERACTION WITH TP53 AND RRM1. RX PubMed=12615712; RA Xue L., Zhou B., Liu X., Qiu W., Jin Z., Yen Y.; RT "Wild-type p53 regulates human ribonucleotide reductase by protein-protein RT interaction with p53R2 as well as hRRM2 subunits."; RL Cancer Res. 63:980-986(2003). RN [12] RP TISSUE SPECIFICITY. RX PubMed=14583450; RA Zhou B., Liu X., Mo X., Xue L., Darwish D., Qiu W., Shih J., Hwu E.B., RA Luh F., Yen Y.; RT "The human ribonucleotide reductase subunit hRRM2 complements p53R2 in RT response to UV-induced DNA repair in cells with mutant p53."; RL Cancer Res. 63:6583-6594(2003). RN [13] RP CATALYTIC ACTIVITY, AND SUBUNIT. RX PubMed=16376858; DOI=10.1016/j.bbrc.2005.12.019; RA Qiu W., Zhou B., Darwish D., Shao J., Yen Y.; RT "Characterization of enzymatic properties of human ribonucleotide reductase RT holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits."; RL Biochem. Biophys. Res. Commun. 340:428-434(2006). RN [14] RP INVOLVEMENT IN PEOA5. RX PubMed=19664747; DOI=10.1016/j.ajhg.2009.07.009; RA Tyynismaa H., Ylikallio E., Patel M., Molnar M.J., Haller R.G., RA Suomalainen A.; RT "A heterozygous truncating mutation in RRM2B causes autosomal-dominant RT progressive external ophthalmoplegia with multiple mtDNA deletions."; RL Am. J. Hum. Genet. 85:290-295(2009). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [16] RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) IN COMPLEX WITH IRON IONS, AND RP COFACTOR. RX PubMed=19728742; DOI=10.1021/bi9001425; RA Smith P., Zhou B., Ho N., Yuan Y.C., Su L., Tsai S.C., Yen Y.; RT "2.6 A X-ray crystal structure of human p53R2, a p53-inducible RT ribonucleotide reductase."; RL Biochemistry 48:11134-11141(2009). RN [17] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 20-322 IN COMPLEX WITH IRON IONS. RG Structural genomics consortium (SGC); RT "Human ribonucleotide reductase, subunit M2 B."; RL Submitted (FEB-2009) to the PDB data bank. RN [18] RP VARIANTS MTDPS8A ARG-64; GLU-85 DEL; GLY-194; LYS-194 AND PHE-236. RX PubMed=17486094; DOI=10.1038/ng2040; RA Bourdon A., Minai L., Serre V., Jais J.-P., Sarzi E., Aubert S., RA Chretien D., de Lonlay P., Paquis-Flucklinger V., Arakawa H., Nakamura Y., RA Munnich A., Roetig A.; RT "Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase RT (p53R2), causes severe mitochondrial DNA depletion."; RL Nat. Genet. 39:776-780(2007). RN [19] RP VARIANTS MTDPS8A SER-224; ILE-282 AND VAL-317. RX PubMed=18504129; DOI=10.1016/j.nmd.2008.04.006; RA Bornstein B., Area E., Flanigan K.M., Ganesh J., Jayakar P., Swoboda K.J., RA Coku J., Naini A., Shanske S., Tanji K., Hirano M., DiMauro S.; RT "Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene."; RL Neuromuscul. Disord. 18:453-459(2008). RN [20] RP VARIANTS MTDPS8B HIS-110 AND HIS-121. RX PubMed=19667227; DOI=10.1001/archneurol.2009.139; RA Shaibani A., Shchelochkov O.A., Zhang S., Katsonis P., Lichtarge O., RA Wong L.J., Shinawi M.; RT "Mitochondrial neurogastrointestinal encephalopathy due to mutations in RT RRM2B."; RL Arch. Neurol. 66:1028-1032(2009). RN [21] RP VARIANT SER-33. RX PubMed=26741492; DOI=10.1371/journal.pgen.1005679; RA Kohda M., Tokuzawa Y., Kishita Y., Nyuzuki H., Moriyama Y., Mizuno Y., RA Hirata T., Yatsuka Y., Yamashita-Sugahara Y., Nakachi Y., Kato H., RA Okuda A., Tamaru S., Borna N.N., Banshoya K., Aigaki T., Sato-Miyata Y., RA Ohnuma K., Suzuki T., Nagao A., Maehata H., Matsuda F., Higasa K., RA Nagasaki M., Yasuda J., Yamamoto M., Fushimi T., Shimura M., RA Kaiho-Ichimoto K., Harashima H., Yamazaki T., Mori M., Murayama K., RA Ohtake A., Okazaki Y.; RT "A comprehensive genomic analysis reveals the genetic landscape of RT mitochondrial respiratory chain complex deficiencies."; RL PLoS Genet. 12:E1005679-E1005679(2016). RN [22] RP VARIANT RCDFRD ASP-262, AND INVOLVEMENT IN RCDFRD. RX PubMed=32827185; DOI=10.1002/humu.24094; RA Roberts L., Julius S., Dawlat S., Yildiz S., Rebello G., Meldau S., RA Pillay K., Esterhuizen A., Vorster A., Benefeld G., da Rocha J., RA Beighton P., Sellars S.L., Thandrayen K., Pettifor J.M., Ramesar R.S.; RT "Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss RT caused by a mutation in RRM2B."; RL Hum. Mutat. 41:1871-1876(2020). CC -!- FUNCTION: Plays a pivotal role in cell survival by repairing damaged CC DNA in a p53/TP53-dependent manner. Supplies deoxyribonucleotides for CC DNA repair in cells arrested at G1 or G2. Contains an iron-tyrosyl free CC radical center required for catalysis. Forms an active ribonucleotide CC reductase (RNR) complex with RRM1 which is expressed both in resting CC and proliferating cells in response to DNA damage. CC {ECO:0000269|PubMed:10716435, ECO:0000269|PubMed:11517226, CC ECO:0000269|PubMed:11719458}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a 2'-deoxyribonucleoside 5'-diphosphate + [thioredoxin]- CC disulfide + H2O = a ribonucleoside 5'-diphosphate + [thioredoxin]- CC dithiol; Xref=Rhea:RHEA:23252, Rhea:RHEA-COMP:10698, Rhea:RHEA- CC COMP:10700, ChEBI:CHEBI:15377, ChEBI:CHEBI:29950, ChEBI:CHEBI:50058, CC ChEBI:CHEBI:57930, ChEBI:CHEBI:73316; EC=1.17.4.1; CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10014, CC ECO:0000269|PubMed:16376858}; CC -!- COFACTOR: CC Name=Fe cation; Xref=ChEBI:CHEBI:24875; CC Evidence={ECO:0000269|PubMed:19728742}; CC Note=Binds 2 iron ions per subunit. {ECO:0000269|PubMed:19728742}; CC -!- SUBUNIT: Heterotetramer with large (RRM1) subunit. Interacts with CC p53/TP53. Interacts with RRM1 in response to DNA damage. CC {ECO:0000269|PubMed:11517226, ECO:0000269|PubMed:12615712, CC ECO:0000269|PubMed:16376858, ECO:0000269|PubMed:19728742, CC ECO:0000269|Ref.17}. CC -!- INTERACTION: CC Q7LG56; Q13315: ATM; NbExp=3; IntAct=EBI-9009083, EBI-495465; CC Q7LG56; Q00987: MDM2; NbExp=2; IntAct=EBI-9009083, EBI-389668; CC Q7LG56; O43929: ORC4; NbExp=4; IntAct=EBI-9009083, EBI-374889; CC Q7LG56; Q9H4P4: RNF41; NbExp=3; IntAct=EBI-9009083, EBI-2130266; CC Q7LG56; Q7LG56: RRM2B; NbExp=3; IntAct=EBI-9009083, EBI-9009083; CC Q7LG56-1; Q00987: MDM2; NbExp=2; IntAct=EBI-15741413, EBI-389668; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Translocates from CC cytoplasm to nucleus in response to DNA damage. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=1; CC IsoId=Q7LG56-1; Sequence=Displayed; CC Name=2; Synonyms=Long form; CC IsoId=Q7LG56-2; Sequence=VSP_017670; CC Name=3; Synonyms=Short form gamma; CC IsoId=Q7LG56-3; Sequence=VSP_017669; CC Name=4; Synonyms=Short form beta; CC IsoId=Q7LG56-4; Sequence=VSP_017668; CC Name=5; Synonyms=Short form; CC IsoId=Q7LG56-5; Sequence=VSP_017671, VSP_017672; CC Name=6; CC IsoId=Q7LG56-6; Sequence=VSP_053585; CC -!- TISSUE SPECIFICITY: Widely expressed at a high level in skeletal muscle CC and at a weak level in thymus. Expressed in epithelial dysplasias and CC squamous cell carcinoma. {ECO:0000269|PubMed:14583450}. CC -!- INDUCTION: In response to DNA damage in a wild-type p53/TP53-dependent CC manner. {ECO:0000269|PubMed:10716435}. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 8A (MTDPS8A) CC [MIM:612075]: A disorder due to mitochondrial dysfunction characterized CC by various combinations of neonatal hypotonia, neurological CC deterioration, respiratory distress, lactic acidosis, and renal CC tubulopathy. {ECO:0000269|PubMed:17486094, CC ECO:0000269|PubMed:18504129}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 8B (MTDPS8B) CC [MIM:612075]: A disease due to mitochondrial dysfunction and CC characterized by ophthalmoplegia, ptosis, gastrointestinal dysmotility, CC cachexia, peripheral neuropathy. {ECO:0000269|PubMed:19667227}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 5 (PEOA5) [MIM:613077]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:19664747}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Rod-cone dystrophy, sensorineural deafness, and Fanconi-type CC renal dysfunction (RCDFRD) [MIM:268315]: An autosomal recessive disease CC characterized by visual impairment due to rod-cone dystrophy, CC sensorineural hearing loss, and Fanconi-type renal dysfunction CC resulting in rickets-like skeletal changes. Death may occur in CC childhood or young adulthood due to renal failure. Disease onset is CC before age 5 years. {ECO:0000269|PubMed:32827185}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 5]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the ribonucleoside diphosphate reductase small CC chain family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAG65196.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=EAW91842.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB036063; BAA92434.1; -; mRNA. DR EMBL; AB036532; BAA92493.1; -; Genomic_DNA. DR EMBL; AB163437; BAD11774.1; -; mRNA. DR EMBL; AB163438; BAD11775.1; -; mRNA. DR EMBL; AB166669; BAD12265.1; -; mRNA. DR EMBL; AB166670; BAD12266.1; -; mRNA. DR EMBL; AB166671; BAD12267.1; -; mRNA. DR EMBL; AK001965; BAA92005.1; -; mRNA. DR EMBL; AK304354; BAG65196.1; ALT_INIT; mRNA. DR EMBL; DC308409; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AL137348; CAB70703.2; -; mRNA. DR EMBL; DQ027001; AAY29059.1; -; Genomic_DNA. DR EMBL; AP001328; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP002907; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471060; EAW91842.1; ALT_SEQ; Genomic_DNA. DR EMBL; BC042468; AAH42468.1; -; mRNA. DR EMBL; BC108261; AAI08262.1; -; mRNA. DR EMBL; BC117496; AAI17497.1; -; mRNA. DR EMBL; BC130628; AAI30629.1; -; mRNA. DR CCDS; CCDS34932.1; -. [Q7LG56-1] DR CCDS; CCDS55267.1; -. [Q7LG56-2] DR PIR; T46249; T46249. DR RefSeq; NP_001165948.1; NM_001172477.1. [Q7LG56-6] DR RefSeq; NP_001165949.1; NM_001172478.2. [Q7LG56-2] DR RefSeq; NP_056528.2; NM_015713.4. [Q7LG56-1] DR PDB; 2VUX; X-ray; 2.80 A; A/B=20-322. DR PDB; 3HF1; X-ray; 2.60 A; A/B=1-351. DR PDB; 4DJN; X-ray; 2.20 A; A/B=13-322. DR PDBsum; 2VUX; -. DR PDBsum; 3HF1; -. DR PDBsum; 4DJN; -. DR AlphaFoldDB; Q7LG56; -. DR SMR; Q7LG56; -. DR BioGRID; 119071; 74. DR ComplexPortal; CPX-369; Ribonucleoside-diphosphate reductase RR1 complex, RRM2B variant. DR CORUM; Q7LG56; -. DR DIP; DIP-24264N; -. DR DIP; DIP-48627N; -. DR FunCoup; Q7LG56; 2091. DR IntAct; Q7LG56; 34. DR STRING; 9606.ENSP00000251810; -. DR BindingDB; Q7LG56; -. DR ChEMBL; CHEMBL3301398; -. DR DrugBank; DB00242; Cladribine. DR DrugBank; DB00631; Clofarabine. DR DrugBank; DB12948; Didox. DR GlyGen; Q7LG56; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q7LG56; -. DR PhosphoSitePlus; Q7LG56; -. DR BioMuta; RRM2B; -. DR DMDM; 74727333; -. DR jPOST; Q7LG56; -. DR MassIVE; Q7LG56; -. DR PaxDb; 9606-ENSP00000251810; -. DR PeptideAtlas; Q7LG56; -. DR ProteomicsDB; 5837; -. DR ProteomicsDB; 68860; -. [Q7LG56-1] DR ProteomicsDB; 68861; -. [Q7LG56-2] DR ProteomicsDB; 68862; -. [Q7LG56-3] DR ProteomicsDB; 68863; -. [Q7LG56-4] DR ProteomicsDB; 68864; -. [Q7LG56-5] DR Pumba; Q7LG56; -. DR Antibodypedia; 3483; 343 antibodies from 38 providers. DR DNASU; 50484; -. DR Ensembl; ENST00000251810.8; ENSP00000251810.3; ENSG00000048392.14. [Q7LG56-1] DR Ensembl; ENST00000395912.6; ENSP00000379248.2; ENSG00000048392.14. [Q7LG56-2] DR Ensembl; ENST00000519317.5; ENSP00000430641.1; ENSG00000048392.14. [Q7LG56-3] DR Ensembl; ENST00000519962.5; ENSP00000429140.1; ENSG00000048392.14. [Q7LG56-4] DR Ensembl; ENST00000522394.1; ENSP00000429578.1; ENSG00000048392.14. [Q7LG56-5] DR GeneID; 50484; -. DR KEGG; hsa:50484; -. DR MANE-Select; ENST00000251810.8; ENSP00000251810.3; NM_015713.5; NP_056528.2. DR UCSC; uc003ykn.4; human. [Q7LG56-1] DR AGR; HGNC:17296; -. DR ClinPGx; PA34866; -. DR CTD; 50484; -. DR DisGeNET; 50484; -. DR GeneCards; RRM2B; -. DR GeneReviews; RRM2B; -. DR HGNC; HGNC:17296; RRM2B. DR HPA; ENSG00000048392; Low tissue specificity. DR MalaCards; RRM2B; -. DR MIM; 268315; phenotype. DR MIM; 604712; gene. DR MIM; 612075; phenotype. DR MIM; 613077; phenotype. DR OpenTargets; ENSG00000048392; -. DR Orphanet; 329336; Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 480; Kearns-Sayre syndrome. DR Orphanet; 255235; Mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy. DR Orphanet; 298; Mitochondrial neurogastrointestinal encephalomyopathy. DR VEuPathDB; HostDB:ENSG00000048392; -. DR eggNOG; KOG1567; Eukaryota. DR GeneTree; ENSGT00390000013305; -. DR HOGENOM; CLU_035339_2_0_1; -. DR InParanoid; Q7LG56; -. DR OMA; LEPMFLG; -. DR OrthoDB; 10248373at2759; -. DR PAN-GO; Q7LG56; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q7LG56; -. DR BRENDA; 1.17.4.1; 2681. DR PathwayCommons; Q7LG56; -. DR Reactome; R-HSA-499943; Interconversion of nucleotide di- and triphosphates. DR Reactome; R-HSA-5628897; TP53 Regulates Metabolic Genes. DR SignaLink; Q7LG56; -. DR SIGNOR; Q7LG56; -. DR Agora; ENSG00000048392; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 50484; 17 hits in 1170 CRISPR screens. DR ChiTaRS; RRM2B; human. DR EvolutionaryTrace; Q7LG56; -. DR GeneWiki; RRM2B; -. DR GenomeRNAi; 50484; -. DR Pharos; Q7LG56; Tbio. DR PRO; PR:Q7LG56; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; Q7LG56; protein. DR Bgee; ENSG00000048392; Expressed in secondary oocyte and 188 other cell types or tissues. DR ExpressionAtlas; Q7LG56; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005739; C:mitochondrion; IEA:GOC. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005971; C:ribonucleoside-diphosphate reductase complex; ISS:ComplexPortal. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0004748; F:ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor; IBA:GO_Central. DR GO; GO:0009265; P:2'-deoxyribonucleotide biosynthetic process; IDA:ComplexPortal. DR GO; GO:0009200; P:deoxyribonucleoside triphosphate metabolic process; IEA:Ensembl. DR GO; GO:0009263; P:deoxyribonucleotide biosynthetic process; IBA:GO_Central. DR GO; GO:0006281; P:DNA repair; IDA:ComplexPortal. DR GO; GO:0000731; P:DNA synthesis involved in DNA repair; NAS:ComplexPortal. DR GO; GO:0001822; P:kidney development; IEA:Ensembl. DR GO; GO:0006264; P:mitochondrial DNA replication; IMP:ComplexPortal. DR GO; GO:1902254; P:negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; IEA:Ensembl. DR GO; GO:0070318; P:positive regulation of G0 to G1 transition; IDA:ComplexPortal. DR GO; GO:0010971; P:positive regulation of G2/M transition of mitotic cell cycle; IDA:ComplexPortal. DR GO; GO:0003014; P:renal system process; IEA:Ensembl. DR GO; GO:0014075; P:response to amine; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl. DR GO; GO:0009185; P:ribonucleoside diphosphate metabolic process; IDA:ComplexPortal. DR CDD; cd01049; RNRR2; 1. DR FunFam; 1.10.620.20:FF:000004; Ribonucleoside-diphosphate reductase subunit M2 B; 1. DR Gene3D; 1.10.620.20; Ribonucleotide Reductase, subunit A; 1. DR InterPro; IPR009078; Ferritin-like_SF. DR InterPro; IPR012348; RNR-like. DR InterPro; IPR033909; RNR_small. DR InterPro; IPR030475; RNR_small_AS. DR InterPro; IPR000358; RNR_small_fam. DR PANTHER; PTHR23409; RIBONUCLEOSIDE-DIPHOSPHATE REDUCTASE SMALL CHAIN; 1. DR PANTHER; PTHR23409:SF19; RIBONUCLEOSIDE-DIPHOSPHATE REDUCTASE SUBUNIT M2 B; 1. DR Pfam; PF00268; Ribonuc_red_sm; 1. DR SUPFAM; SSF47240; Ferritin-like; 1. DR PROSITE; PS00368; RIBORED_SMALL; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Deafness; KW Deoxyribonucleotide synthesis; Disease variant; DNA damage; DNA repair; KW Iron; Metal-binding; Neuropathy; Nucleus; Oxidoreductase; KW Primary mitochondrial disease; Progressive external ophthalmoplegia; KW Proteomics identification; Reference proteome. FT CHAIN 1..351 FT /note="Ribonucleoside-diphosphate reductase subunit M2 B" FT /id="PRO_0000228150" FT REGION 1..32 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 138 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10014" FT BINDING 100 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="1" FT BINDING 131 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="1" FT BINDING 131 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="2" FT BINDING 134 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="1" FT BINDING 194 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="2" FT BINDING 228 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="2" FT BINDING 231 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="2" FT VAR_SEQ 1..16 FT /note="MGDPERPEAAGLDQDE -> MLLLRLPPHRSHASPLDCKLQDRCRKCYSPRS FT GQACPPALAAAWLRRCERRGGRPRGGRRKELTLGLRPARCSAPGPAKDDAWRPQAG FT (in isoform 6)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_053585" FT VAR_SEQ 17..301 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017668" FT VAR_SEQ 17..228 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017669" FT VAR_SEQ 17..68 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017670" FT VAR_SEQ 42..43 FT /note="FV -> SF (in isoform 5)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017671" FT VAR_SEQ 44..351 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017672" FT VARIANT 33 FT /note="P -> S (found in a patient with combined respiratory FT complex deficiencies, muscle weakness and hearing loss; FT uncertain significance; dbSNP:rs387906892)" FT /evidence="ECO:0000269|PubMed:26741492" FT /id="VAR_076280" FT VARIANT 64 FT /note="W -> R (in MTDPS8A; dbSNP:rs515726182)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046217" FT VARIANT 85 FT /note="Missing (in MTDPS8A; dbSNP:rs515726184)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046218" FT VARIANT 110 FT /note="R -> H (in MTDPS8B; dbSNP:rs267607025)" FT /evidence="ECO:0000269|PubMed:19667227" FT /id="VAR_065122" FT VARIANT 115 FT /note="V -> L (in colorectal adenocarcinomas cell line; FT loss of ribonucleotide reductase activity)" FT /evidence="ECO:0000269|PubMed:11719458" FT /id="VAR_025699" FT VARIANT 121 FT /note="R -> H (in MTDPS8B; dbSNP:rs267607024)" FT /evidence="ECO:0000269|PubMed:19667227" FT /id="VAR_065123" FT VARIANT 194 FT /note="E -> G (in MTDPS8A; dbSNP:rs515726191)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046219" FT VARIANT 194 FT /note="E -> K (in MTDPS8A; dbSNP:rs121918308)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046220" FT VARIANT 224 FT /note="I -> S (in MTDPS8A; without tubulopathy; FT dbSNP:rs515726196)" FT /evidence="ECO:0000269|PubMed:18504129" FT /id="VAR_046221" FT VARIANT 236 FT /note="C -> F (in MTDPS8A; dbSNP:rs121918309)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046222" FT VARIANT 262 FT /note="E -> D (in RCDFRD; dbSNP:rs1810682433)" FT /evidence="ECO:0000269|PubMed:32827185" FT /id="VAR_086956" FT VARIANT 282 FT /note="M -> I (in MTDPS8A; without tubulopathy; FT dbSNP:rs182614164)" FT /evidence="ECO:0000269|PubMed:18504129" FT /id="VAR_046223" FT VARIANT 317 FT /note="L -> V (in MTDPS8A; without tubulopathy; FT dbSNP:rs515726198)" FT /evidence="ECO:0000269|PubMed:18504129" FT /id="VAR_046224" FT CONFLICT 277 FT /note="M -> V (in Ref. 3; BAA92005)" FT /evidence="ECO:0000305" FT HELIX 29..31 FT /evidence="ECO:0007829|PDB:4DJN" FT TURN 33..35 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 37..39 FT /evidence="ECO:0007829|PDB:4DJN" FT STRAND 42..44 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 50..61 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 66..68 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 74..78 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 83..109 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 111..114 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 118..145 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 149..156 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 158..161 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 163..177 FT /evidence="ECO:0007829|PDB:4DJN" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 183..195 FT /evidence="ECO:0007829|PDB:4DJN" FT TURN 196..198 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 199..210 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 215..240 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 248..267 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 272..275 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 279..296 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 310..312 FT /evidence="ECO:0007829|PDB:4DJN" SQ SEQUENCE 351 AA; 40737 MW; 6D008687EEF40994 CRC64; MGDPERPEAA GLDQDERSSS DTNESEIKSN EEPLLRKSSR RFVIFPIQYP DIWKMYKQAQ ASFWTAEEVD LSKDLPHWNK LKADEKYFIS HILAFFAASD GIVNENLVER FSQEVQVPEA RCFYGFQILI ENVHSEMYSL LIDTYIRDPK KREFLFNAIE TMPYVKKKAD WALRWIADRK STFGERVVAF AAVEGVFFSG SFAAIFWLKK RGLMPGLTFS NELISRDEGL HCDFACLMFQ YLVNKPSEER VREIIVDAVK IEQEFLTEAL PVGLIGMNCI LMKQYIEFVA DRLLVELGFS KVFQAENPFD FMENISLEGK TNFFEKRVSE YQRFAVMAET TDNVFTLDAD F //