ID CNR1_HUMAN Reviewed; 472 AA. AC P21554; B2R9T4; E1P512; Q13949; Q495Z0; Q4PLI4; Q4VBM6; Q5JVL5; Q5UB37; AC Q9UNN0; DT 01-MAY-1991, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1991, sequence version 1. DT 28-JAN-2026, entry version 234. DE RecName: Full=Cannabinoid receptor 1; DE Short=CB-R; DE Short=CB1; DE AltName: Full=CANN6; GN Name=CNR1; Synonyms=CNR; 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] (ISOFORM 1). RC TISSUE=Brain stem; RX PubMed=2263478; DOI=10.1093/nar/18.23.7142; RA Gerard C., Mollereau C., Vassart G., Parmentier M.; RT "Nucleotide sequence of a human cannabinoid receptor cDNA."; RL Nucleic Acids Res. 18:7142-7142(1990). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION. RC TISSUE=Brain stem; RX PubMed=1718258; DOI=10.1042/bj2790129; RA Gerard C., Mollereau C., Vassart G., Parmentier M.; RT "Molecular cloning of a human cannabinoid receptor which is also expressed RT in testis."; RL Biochem. J. 279:129-134(1991). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Lung; RX PubMed=7876112; DOI=10.1074/jbc.270.8.3726; RA Shire D., Carillon C., Kaghad M., Calandra B., Rinaldi-Carmona M., RA Le Fur G., Caput D., Ferrara P.; RT "An amino-terminal variant of the central cannabinoid receptor resulting RT from alternative splicing."; RL J. Biol. Chem. 270:3726-3731(1995). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION (ISOFORMS 1; 2 AND 3), AND RP TISSUE SPECIFICITY. RC TISSUE=Fetal brain; RX PubMed=15620723; DOI=10.1016/j.febslet.2004.11.085; RA Ryberg E., Vu H.K., Larsson N., Groblewski T., Hjorth S., Elebring T., RA Sjoegren S., Greasley P.J.; RT "Identification and characterisation of a novel splice variant of the human RT CB1 receptor."; RL FEBS Lett. 579:259-264(2005). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Hippocampus; RA Kathmann M., Schlicker E.; RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Bonner T.I.; RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain tumor; RA Kumar S., Gupta S., Sharma G.; RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Kopatz S.A., Aronstam R.S., Sharma S.V.; RT "cDNA clones of human proteins involved in signal transduction sequenced by RT the Guthrie cDNA resource center (www.cdna.org)."; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Hippocampus; 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 [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [11] 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 [12] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Lung; 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 [13] RP REVIEW ON INVOLVEMENT IN NERVOUS SYSTEM DISORDERS. RX PubMed=32549916; DOI=10.1007/s13167-020-00203-4; RA Reddy V., Grogan D., Ahluwalia M., Salles E.L., Ahluwalia P., Khodadadi H., RA Alverson K., Nguyen A., Raju S.P., Gaur P., Braun M., Vale F.L., RA Costigliola V., Dhandapani K., Baban B., Vaibhav K.; RT "Targeting the endocannabinoid system: a predictive, preventive, and RT personalized medicine-directed approach to the management of brain RT pathologies."; RL EPMA J. 11:217-250(2020). RN [14] RP INVOLVEMENT IN HUNTINGTON DISEASE. RX PubMed=8255419; DOI=10.1016/0306-4522(93)90352-g; RA Glass M., Faull R.L., Dragunow M.; RT "Loss of cannabinoid receptors in the substantia nigra in Huntington's RT disease."; RL Neuroscience 56:523-527(1993). RN [15] RP INVOLVEMENT IN HUNTINGTON DISEASE. RX PubMed=10828533; DOI=10.1016/s0306-4522(00)00008-7; RA Glass M., Dragunow M., Faull R.L.; RT "The pattern of neurodegeneration in Huntington's disease: a comparative RT study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations RT in the human basal ganglia in Huntington's disease."; RL Neuroscience 97:505-519(2000). RN [16] RP FUNCTION, AND INTERACTION WITH CNRIP1. RC TISSUE=Brain; RX PubMed=17895407; DOI=10.1124/mol.107.039263; RA Niehaus J.L., Liu Y., Wallis K.T., Egertova M., Bhartur S.G., RA Mukhopadhyay S., Shi S., He H., Selley D.E., Howlett A.C., Elphick M.R., RA Lewis D.L.; RT "CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor RT interacting protein CRIP 1a."; RL Mol. Pharmacol. 72:1557-1566(2007). RN [17] RP ACTIVITY REGULATION. RX PubMed=18077343; DOI=10.1073/pnas.0706980105; RA Heimann A.S., Gomes I., Dale C.S., Pagano R.L., Gupta A., de Souza L.L., RA Luchessi A.D., Castro L.M., Giorgi R., Rioli V., Ferro E.S., Devi L.A.; RT "Hemopressin is an inverse agonist of CB1 cannabinoid receptors."; RL Proc. Natl. Acad. Sci. U.S.A. 104:20588-20593(2007). RN [18] RP FUNCTION, SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-415, AND MUTAGENESIS RP OF CYS-415. RX PubMed=21895628; DOI=10.1111/j.1476-5381.2011.01658.x; RA Oddi S., Dainese E., Sandiford S., Fezza F., Lanuti M., Chiurchiu V., RA Totaro A., Catanzaro G., Barcaroli D., De Laurenzi V., Centonze D., RA Mukhopadhyay S., Selent J., Howlett A.C., Maccarrone M.; RT "Effects of palmitoylation of Cys(415) in helix 8 of the CB(1) cannabinoid RT receptor on membrane localization and signalling."; RL Br. J. Pharmacol. 165:2635-2651(2012). RN [19] RP INVOLVEMENT IN OBESITY. RX PubMed=18177726; DOI=10.1016/j.cmet.2007.11.012; RA Addy C., Wright H., Van Laere K., Gantz I., Erondu N., Musser B.J., Lu K., RA Yuan J., Sanabria-Bohorquez S.M., Stoch A., Stevens C., Fong T.M., RA De Lepeleire I., Cilissen C., Cote J., Rosko K., Gendrano I.N. III, RA Nguyen A.M., Gumbiner B., Rothenberg P., de Hoon J., Bormans G., Depre M., RA Eng W.S., Ravussin E., Klein S., Blundell J., Herman G.A., Burns H.D., RA Hargreaves R.J., Wagner J., Gottesdiener K., Amatruda J.M., RA Heymsfield S.B.; RT "The acyclic CB1R inverse agonist taranabant mediates weight loss by RT increasing energy expenditure and decreasing caloric intake."; RL Cell Metab. 7:68-78(2008). RN [20] RP INVOLVEMENT IN HUNTINGTON DISEASE. RX PubMed=19524019; DOI=10.1016/j.neuroscience.2009.06.014; RA Dowie M.J., Bradshaw H.B., Howard M.L., Nicholson L.F., Faull R.L., RA Hannan A.J., Glass M.; RT "Altered CB1 receptor and endocannabinoid levels precede motor symptom RT onset in a transgenic mouse model of Huntington's disease."; RL Neuroscience 163:456-465(2009). RN [21] RP FUNCTION, AND INDUCTION BY ENDOCANNABINOID ANANDAMIDE. RX PubMed=23955712; DOI=10.1038/nm.3265; RA Jourdan T., Godlewski G., Cinar R., Bertola A., Szanda G., Liu J., Tam J., RA Han T., Mukhopadhyay B., Skarulis M.C., Ju C., Aouadi M., Czech M.P., RA Kunos G.; RT "Activation of the Nlrp3 inflammasome in infiltrating macrophages by RT endocannabinoids mediates beta cell loss in type 2 diabetes."; RL Nat. Med. 19:1132-1140(2013). RN [22] RP INVOLVEMENT IN ALZHEIMER DISEASE. RX PubMed=30096288; DOI=10.1016/j.bcp.2018.08.007; RA Aso E., Andres-Benito P., Ferrer I.; RT "Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer- RT like symptoms in a transgenic animal model."; RL Biochem. Pharmacol. 157:210-216(2018). RN [23] RP INVOLVEMENT IN PARKINSON DISEASE. RX PubMed=31342135; DOI=10.1007/s00259-019-04445-x; RA Ceccarini J., Casteels C., Ahmad R., Crabbe M., Van de Vliet L., RA Vanhaute H., Vandenbulcke M., Vandenberghe W., Van Laere K.; RT "Regional changes in the type 1 cannabinoid receptor are associated with RT cognitive dysfunction in Parkinson's disease."; RL Eur. J. Nucl. Med. Mol. Imaging 46:2348-2357(2019). RN [24] RP STRUCTURE BY NMR OF 338-346, INTERACTION WITH GNAI1, AND MUTAGENESIS OF RP 341-LEU-ALA-342. RX PubMed=12237474; DOI=10.1110/ps.0218402; RA Ulfers A.L., McMurry J.L., Miller A., Wang L., Kendall D.A., Mierke D.F.; RT "Cannabinoid receptor-G protein interactions: G(alphai1)-bound structures RT of IC3 and a mutant with altered G protein specificity."; RL Protein Sci. 11:2526-2531(2002). RN [25] {ECO:0007744|PDB:5TGZ} RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 99-306 AND 332-414, FUNCTION, AND RP TOPOLOGY. RX PubMed=27768894; DOI=10.1016/j.cell.2016.10.004; RA Hua T., Vemuri K., Pu M., Qu L., Han G.W., Wu Y., Zhao S., Shui W., Li S., RA Korde A., Laprairie R.B., Stahl E.L., Ho J.H., Zvonok N., Zhou H., RA Kufareva I., Wu B., Zhao Q., Hanson M.A., Bohn L.M., Makriyannis A., RA Stevens R.C., Liu Z.J.; RT "Crystal structure of the human cannabinoid receptor CB1."; RL Cell 167:750-762(2016). RN [26] {ECO:0007744|PDB:5U09} RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 90-301 AND 334-421 IN COMPLEX RP WITH INVERSE AGONIST TARANABANT, MUTAGENESIS OF THR-210, TOPOLOGY, AND RP FUNCTION. RX PubMed=27851727; DOI=10.1038/nature20613; RA Shao Z., Yin J., Chapman K., Grzemska M., Clark L., Wang J., RA Rosenbaum D.M.; RT "High-resolution crystal structure of the human CB1 cannabinoid receptor."; RL Nature 540:602-606(2016). RN [27] {ECO:0007744|PDB:7FEE, ECO:0007744|PDB:7WV9} RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 74-305 AND 333-414, INTERACTION RP WITH GNAI2, FUNCTION, AND MUTAGENESIS OF PHE-155. RX PubMed=35637350; DOI=10.1038/s41589-022-01038-y; RA Yang X., Wang X., Xu Z., Wu C., Zhou Y., Wang Y., Lin G., Li K., Wu M., RA Xia A., Liu J., Cheng L., Zou J., Yan W., Shao Z., Yang S.; RT "Molecular mechanism of allosteric modulation for the cannabinoid receptor RT CB1."; RL Nat. Chem. Biol. 18:831-840(2022). CC -!- FUNCTION: G-protein coupled receptor for endogenous cannabinoids CC (eCBs), including N-arachidonoylethanolamide (also called anandamide or CC AEA) and 2-arachidonoylglycerol (2-AG), as well as phytocannabinoids, CC such as delta(9)-tetrahydrocannabinol (THC) (PubMed:15620723, CC PubMed:27768894, PubMed:27851727, PubMed:35637350). Mediates many CC cannabinoid-induced effects, acting, among others, on food intake, CC memory loss, gastrointestinal motility, catalepsy, ambulatory activity, CC anxiety, chronic pain. Signaling typically involves reduction in cyclic CC AMP (PubMed:1718258, PubMed:21895628, PubMed:27768894). In the CC hypothalamus, may have a dual effect on mitochondrial respiration CC depending upon the agonist dose and possibly upon the cell type. CC Increases respiration at low doses, while decreases respiration at high CC doses. At high doses, CNR1 signal transduction involves G-protein CC alpha-i protein activation and subsequent inhibition of mitochondrial CC soluble adenylate cyclase, decrease in cyclic AMP concentration, CC inhibition of protein kinase A (PKA)-dependent phosphorylation of CC specific subunits of the mitochondrial electron transport system, CC including NDUFS2. In the hypothalamus, inhibits leptin-induced reactive CC oxygen species (ROS) formation and mediates cannabinoid-induced CC increase in SREBF1 and FASN gene expression. In response to CC cannabinoids, drives the release of orexigenic beta-endorphin, but not CC that of melanocyte-stimulating hormone alpha/alpha-MSH, from CC hypothalamic POMC neurons, hence promoting food intake. In the CC hippocampus, regulates cellular respiration and energy production in CC response to cannabinoids. Involved in cannabinoid-dependent CC depolarization-induced suppression of inhibition (DSI), a process in CC which depolarization of CA1 postsynaptic pyramidal neurons mobilizes CC eCBs, which retrogradely activate presynaptic CB1 receptors, CC transiently decreasing GABAergic inhibitory neurotransmission. Also CC reduces excitatory synaptic transmission (By similarity). In superior CC cervical ganglions and cerebral vascular smooth muscle cells, inhibits CC voltage-gated Ca(2+) channels in a constitutive, as well as agonist- CC dependent manner (PubMed:17895407). In cerebral vascular smooth muscle CC cells, cannabinoid-induced inhibition of voltage-gated Ca(2+) channels CC leads to vasodilation and decreased vascular tone (By similarity). CC Induces leptin production in adipocytes and reduces LRP2-mediated CC leptin clearance in the kidney, hence participating in hyperleptinemia. CC In adipose tissue, CNR1 signaling leads to increased expression of CC SREBF1, ACACA and FASN genes (By similarity). In the liver, activation CC by endocannabinoids leads to increased de novo lipogenesis and reduced CC fatty acid catabolism, associated with increased expression of CC SREBF1/SREBP-1, GCK, ACACA, ACACB and FASN genes. May also affect de CC novo cholesterol synthesis and HDL-cholesteryl ether uptake. CC Peripherally modulates energy metabolism (By similarity). In high CC carbohydrate diet-induced obesity, may decrease the expression of CC mitochondrial dihydrolipoyl dehydrogenase/DLD in striated muscles, as CC well as that of selected glucose/ pyruvate metabolic enzymes, hence CC affecting energy expenditure through mitochondrial metabolism (By CC similarity). In response to cannabinoid anandamide, elicits a pro- CC inflammatory response in macrophages, which involves NLRP3 inflammasome CC activation and IL1B and IL18 secretion (By similarity). In macrophages CC infiltrating pancreatic islets, this process may participate in the CC progression of type-2 diabetes and associated loss of pancreatic beta- CC cells (PubMed:23955712). {ECO:0000250|UniProtKB:O02777, CC ECO:0000250|UniProtKB:P47746, ECO:0000269|PubMed:15620723, CC ECO:0000269|PubMed:1718258, ECO:0000269|PubMed:17895407, CC ECO:0000269|PubMed:21895628, ECO:0000269|PubMed:23955712, CC ECO:0000269|PubMed:27768894, ECO:0000269|PubMed:27851727, CC ECO:0000269|PubMed:35637350}. CC -!- FUNCTION: [Isoform 1]: Binds both 2-arachidonoylglycerol (2-AG) and CC anandamide. {ECO:0000269|PubMed:15620723}. CC -!- FUNCTION: [Isoform 2]: Only binds 2-arachidonoylglycerol (2-AG) with CC high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an CC inverse agonist on isoform 2 in assays measuring GTP binding to CC membranes. {ECO:0000269|PubMed:15620723}. CC -!- FUNCTION: [Isoform 3]: Only binds 2-arachidonoylglycerol (2-AG) with CC high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an CC inverse agonist on isoform 3 in assays measuring GTP binding to CC membranes. {ECO:0000269|PubMed:15620723}. CC -!- ACTIVITY REGULATION: Hemopressin, a peptide derived from hemoglobin CC subunit alpha (HBA1 and/or HBA2), acts as an antagonist peptide: CC hemopressin-binding efficiently blocks cannabinoid receptor CNR1 and CC subsequent signaling. {ECO:0000269|PubMed:18077343}. CC -!- SUBUNIT: Interacts (via C-terminus) with CNRIP1; this interaction CC attenuates constitutive, but not agonist-dependent, inhibition of CC voltage-gated Ca(2+) channels in neurons (PubMed:17895407). Associates CC with G protein alpha subunits, including G(i) alpha-1/GNAI1, G(i) CC alpha-2/GNAI2, G(i) alpha-3/GNAI3 and G(o)-alpha/GNAO1; palmitoylation CC is important for interaction with GNAI3 and GNAO1 (PubMed:12237474). CC {ECO:0000269|PubMed:12237474, ECO:0000269|PubMed:17895407, CC ECO:0000269|PubMed:35637350}. CC -!- INTERACTION: CC P21554; P29274: ADORA2A; NbExp=8; IntAct=EBI-2909859, EBI-2902702; CC P21554; P21554: CNR1; NbExp=8; IntAct=EBI-2909859, EBI-2909859; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:21895628}; CC Multi-pass membrane protein {ECO:0000269|PubMed:27768894, CC ECO:0000269|PubMed:27851727}. Membrane raft CC {ECO:0000269|PubMed:21895628}. Mitochondrion outer membrane CC {ECO:0000250|UniProtKB:P47746}. Cell projection, axon CC {ECO:0000250|UniProtKB:P20272}. Presynapse CC {ECO:0000250|UniProtKB:P20272}. Note=Unexpectedly, in the mitochondria, CC the C-terminus is located in the mitochondrial intermembrane space, a CC compartment topologically considered as extracellular. In canonical CC seven-transmembrane G-protein coupled receptors, the C-terminus is CC cytosolic (By similarity). Found on presynaptic axon terminals in some CC GABAergic neurons in the somatosensory cortex (By similarity). CC {ECO:0000250|UniProtKB:P20272, ECO:0000250|UniProtKB:P47746}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=Long; CC IsoId=P21554-1; Sequence=Displayed; CC Name=2; Synonyms=CB1a {ECO:0000303|PubMed:15620723}, Short; CC IsoId=P21554-2; Sequence=VSP_001868; CC Name=3; Synonyms=CB1b {ECO:0000303|PubMed:15620723}; CC IsoId=P21554-3; Sequence=VSP_016529; CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in fetal and CC adult brain. Expression levels of isoform 2 and isoform 3 are much CC lower than those of isoform 1. {ECO:0000269|PubMed:15620723}. CC -!- INDUCTION: Up-regulated by endocannabinoid anandamide. CC {ECO:0000269|PubMed:23955712}. CC -!- PTM: Palmitoylation at Cys-415 is important for recruitment at plasma CC membrane and lipid rafts and association with G protein alpha subunits. CC {ECO:0000269|PubMed:21895628}. CC -!- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by CC an increase of body weight beyond the limitation of skeletal and CC physical requirements, as the result of excessive accumulation of body CC fat. {ECO:0000269|PubMed:18177726}. Note=The protein represented in CC this entry may be involved in disease pathogenesis. May contribute to CC the development of diet-induced obesity and several obesity-associated CC features, such as dyslipidemia and liver steatosis, regulating CC peripheral lipogenesis, energy expenditure and feeding behavior. CNR1 CC inverse agonists have been shown to reduce body weight and improve CC metabolic abnormalities in obese subjects, although adverse CC neuropsychiatric effects, including anxiety, irritability, and CC depressed mood, halted their therapeutic development (PubMed:18177726). CC In obese mice, peripherally restricted CNR1 inverse agonists have been CC shown to normalize metabolic abnormalities, including insulin CC resistance and fatty liver, and to reverse leptin resistance. CC {ECO:0000269|PubMed:18177726}. CC -!- DISEASE: Note=Dysfunction of the endogenous cannabinoid system CC including CNR1 has been implicated in the pathogenesis of a number of CC central nervous system disorders, including Huntington disease, CC Parkinson disease, and Alzheimer disease (PubMed:32549916). In post- CC mortem brains from Huntington disease patients, a progressive CNR1 loss CC has been observed in the caudate nucleus, putamen, and substantia nigra CC pars reticulata, and altered expression and abnormal endocannabinoid CC levels precede motor symptoms in a disease mouse model CC (PubMed:10828533, PubMed:19524019, PubMed:8255419). In Parkinson CC disease, low CNR1 expression in mid-superior frontal gyrus and mid- CC cingulate cortex has been associated with poor mind, poor executive CC functioning and poor episode memory, while patients with more severe CC visuospatial dysfunction showed decreased receptor availability in the CC precuneus, mid-cingulate, supplementary motor cortex, inferior CC orbitofrontal gyrus and thalamus (PubMed:31342135). In an animal model CC for Alzheimer disease, CNR1 heterozygous deletion has been associated CC with decreased levels of postsynaptic density protein 95 (DLG4/PSD95) CC and accelerated memory impairment, suggesting synaptic dysfunction and CC a crucial role for CNR1 in the progression of disease symptoms CC (PubMed:10828533, PubMed:19524019, PubMed:30096288, PubMed:31342135, CC PubMed:8255419). {ECO:0000269|PubMed:10828533, CC ECO:0000269|PubMed:19524019, ECO:0000269|PubMed:30096288, CC ECO:0000269|PubMed:31342135, ECO:0000269|PubMed:32549916, CC ECO:0000269|PubMed:8255419}. CC -!- MISCELLANEOUS: High-fat diet also increases the hepatic levels of CNR1 CC ligand anandamide, but not that of 2-arachidonoylglycerol. CC {ECO:0000250|UniProtKB:P47746}. CC -!- MISCELLANEOUS: [Isoform 2]: Dubious isoform. A putative downstream CC initiation AUG is used to produce isoform 2 (PubMed:1718258). The use CC of the first AUG (same as isoform 1) gives a truncated protein of 36 CC AA. {ECO:0000305|PubMed:1718258}. CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family. CC {ECO:0000255|PROSITE-ProRule:PRU00521}. 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; X54937; CAA38699.1; -; mRNA. DR EMBL; X81120; CAA57018.1; -; mRNA. DR EMBL; X81121; CAA57019.1; -; mRNA. DR EMBL; AY766182; AAV35030.1; -; mRNA. DR EMBL; AF107262; AAD34320.1; -; mRNA. DR EMBL; U73304; AAB18200.1; -; Genomic_DNA. DR EMBL; DQ067455; AAY68486.1; -; mRNA. DR EMBL; AY225225; AAO67710.1; -; Genomic_DNA. DR EMBL; AL136096; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AK313908; BAG36631.1; -; mRNA. DR EMBL; CH471051; EAW48574.1; -; Genomic_DNA. DR EMBL; CH471051; EAW48575.1; -; Genomic_DNA. DR EMBL; CH471051; EAW48576.1; -; Genomic_DNA. DR EMBL; BC074811; AAH74811.1; -; mRNA. DR EMBL; BC074812; AAH74812.1; -; mRNA. DR EMBL; BC095513; AAH95513.1; -; mRNA. DR EMBL; BC100968; AAI00969.1; -; mRNA. DR EMBL; BC100969; AAI00970.1; -; mRNA. DR EMBL; BC100970; AAI00971.1; -; mRNA. DR EMBL; BC100971; AAI00972.1; -; mRNA. DR CCDS; CCDS5015.1; -. [P21554-1] DR CCDS; CCDS5016.2; -. [P21554-3] DR PIR; S17595; S17595. DR RefSeq; NP_001153698.1; NM_001160226.3. [P21554-1] DR RefSeq; NP_001153730.1; NM_001160258.3. [P21554-1] DR RefSeq; NP_001153731.1; NM_001160259.3. [P21554-1] DR RefSeq; NP_001352798.1; NM_001365869.2. [P21554-1] DR RefSeq; NP_001352799.1; NM_001365870.2. [P21554-1] DR RefSeq; NP_001352801.1; NM_001365872.2. [P21554-1] DR RefSeq; NP_001352803.1; NM_001365874.3. [P21554-1] DR RefSeq; NP_001357474.1; NM_001370545.1. [P21554-1] DR RefSeq; NP_001357475.1; NM_001370546.1. [P21554-1] DR RefSeq; NP_001357476.1; NM_001370547.1. [P21554-1] DR RefSeq; NP_001411023.1; NM_001424094.1. [P21554-1] DR RefSeq; NP_001411024.1; NM_001424095.1. [P21554-1] DR RefSeq; NP_001411025.1; NM_001424096.1. [P21554-1] DR RefSeq; NP_001411026.1; NM_001424097.1. [P21554-1] DR RefSeq; NP_001411027.1; NM_001424098.1. [P21554-1] DR RefSeq; NP_057167.2; NM_016083.4. [P21554-1] DR RefSeq; NP_149421.2; NM_033181.4. [P21554-3] DR RefSeq; XP_047274127.1; XM_047418171.1. [P21554-1] DR RefSeq; XP_047274128.1; XM_047418172.1. [P21554-1] DR RefSeq; XP_047274129.1; XM_047418173.1. [P21554-1] DR RefSeq; XP_054210179.1; XM_054354204.1. [P21554-1] DR RefSeq; XP_054210180.1; XM_054354205.1. [P21554-1] DR RefSeq; XP_054210181.1; XM_054354206.1. [P21554-1] DR PDB; 1LVQ; NMR; -; A=338-346. DR PDB; 1LVR; NMR; -; A=338-346. DR PDB; 2B0Y; NMR; -; A=400-414. DR PDB; 2KOE; NMR; -; A=377-414. DR PDB; 2MZ2; NMR; -; A=400-414. DR PDB; 2MZ3; NMR; -; A=400-414. DR PDB; 2MZA; NMR; -; A=400-414. DR PDB; 5TGZ; X-ray; 2.80 A; A=99-306, A=332-414. DR PDB; 5U09; X-ray; 2.60 A; A=90-301, A=333-421. DR PDB; 5XR8; X-ray; 2.95 A; A=99-306, A=332-414. DR PDB; 5XRA; X-ray; 2.80 A; A=99-306, A=332-414. DR PDB; 6KPG; EM; 3.00 A; R=71-425. DR PDB; 6KQI; X-ray; 3.25 A; A=94-301, A=334-413. DR PDB; 6N4B; EM; 3.00 A; R=1-472. DR PDB; 7FEE; X-ray; 2.70 A; A=74-305, A=333-414. DR PDB; 7V3Z; X-ray; 3.29 A; A=102-306, A=336-414. DR PDB; 7WV9; EM; 3.36 A; R=1-472. DR PDB; 8GAG; EM; 3.30 A; R=1-472. DR PDB; 8GHV; EM; 2.80 A; D=1-472. DR PDB; 8IKG; EM; 3.40 A; R=99-408. DR PDB; 8IKH; EM; 3.30 A; R=99-408. DR PDB; 8K8J; EM; 2.88 A; R=71-425. DR PDB; 8WRZ; EM; 3.60 A; R=71-432. DR PDB; 8WU1; EM; 3.20 A; R=1-413. DR PDB; 9B54; EM; 2.86 A; R=1-472. DR PDB; 9B65; EM; 3.03 A; R=1-472. DR PDB; 9B9Y; EM; 3.50 A; R=96-301, R=334-416. DR PDB; 9B9Z; EM; 3.30 A; R=96-301, R=334-416. DR PDB; 9BA0; EM; 3.13 A; R=96-301, R=334-416. DR PDB; 9DGI; EM; 3.35 A; R=1-472. DR PDB; 9EGO; EM; 3.20 A; R=1-472. DR PDB; 9ERX; EM; 2.90 A; R=2-472. DR PDBsum; 1LVQ; -. DR PDBsum; 1LVR; -. DR PDBsum; 2B0Y; -. DR PDBsum; 2KOE; -. DR PDBsum; 2MZ2; -. DR PDBsum; 2MZ3; -. DR PDBsum; 2MZA; -. DR PDBsum; 5TGZ; -. DR PDBsum; 5U09; -. DR PDBsum; 5XR8; -. DR PDBsum; 5XRA; -. DR PDBsum; 6KPG; -. DR PDBsum; 6KQI; -. DR PDBsum; 6N4B; -. DR PDBsum; 7FEE; -. DR PDBsum; 7V3Z; -. DR PDBsum; 7WV9; -. DR PDBsum; 8GAG; -. DR PDBsum; 8GHV; -. DR PDBsum; 8IKG; -. DR PDBsum; 8IKH; -. DR PDBsum; 8K8J; -. DR PDBsum; 8WRZ; -. DR PDBsum; 8WU1; -. DR PDBsum; 9B54; -. DR PDBsum; 9B65; -. DR PDBsum; 9B9Y; -. DR PDBsum; 9B9Z; -. DR PDBsum; 9BA0; -. DR PDBsum; 9DGI; -. DR PDBsum; 9EGO; -. DR PDBsum; 9ERX; -. DR AlphaFoldDB; P21554; -. DR EMDB; EMD-0339; -. DR EMDB; EMD-0745; -. DR EMDB; EMD-19929; -. DR EMDB; EMD-29898; -. DR EMDB; EMD-32850; -. DR EMDB; EMD-35511; -. DR EMDB; EMD-35512; -. DR EMDB; EMD-36951; -. DR EMDB; EMD-37795; -. DR EMDB; EMD-40052; -. DR EMDB; EMD-44199; -. DR EMDB; EMD-44247; -. DR EMDB; EMD-44392; -. DR EMDB; EMD-44393; -. DR EMDB; EMD-44394; -. DR EMDB; EMD-46828; -. DR EMDB; EMD-47992; -. DR SMR; P21554; -. DR BioGRID; 107668; 11. DR CORUM; P21554; -. DR DIP; DIP-61575N; -. DR FunCoup; P21554; 1275. DR IntAct; P21554; 12. DR STRING; 9606.ENSP00000358513; -. DR BindingDB; P21554; -. DR ChEMBL; CHEMBL218; -. DR DrugBank; DB09061; Cannabidiol. DR DrugBank; DB14737; Cannabinol. DR DrugBank; DB05750; Drinabant. DR DrugBank; DB00470; Dronabinol. DR DrugBank; DB14009; Medical Cannabis. DR DrugBank; DB00486; Nabilone. DR DrugBank; DB14011; Nabiximols. DR DrugBank; DB16495; Oleic monoethanolamide. DR DrugBank; DB01083; Orlistat. DR DrugBank; DB11745; Otenabant. DR DrugBank; DB13495; Paraoxon. DR DrugBank; DB09288; Propacetamol. DR DrugBank; DB02955; Ricinoleic acid. DR DrugBank; DB06155; Rimonabant. DR DrugBank; DB05077; SLV319. DR DrugBank; DB13070; Surinabant. DR DrugBank; DB06624; Taranabant. DR DrugBank; DB11755; Tetrahydrocannabivarin. DR DrugBank; DB05201; V24343. DR DrugBank; DB13950; WIN 55212-2. DR DrugCentral; P21554; -. DR GuidetoPHARMACOLOGY; 56; -. DR SwissLipids; SLP:000001607; -. DR TCDB; 9.A.14.2.2; the g-protein-coupled receptor (gpcr) family. DR GlyCosmos; P21554; 2 sites, No reported glycans. DR GlyGen; P21554; 2 sites. DR iPTMnet; P21554; -. DR PhosphoSitePlus; P21554; -. DR SwissPalm; P21554; -. DR BioMuta; CNR1; -. DR DMDM; 115562; -. DR MassIVE; P21554; -. DR PaxDb; 9606-ENSP00000358513; -. DR PeptideAtlas; P21554; -. DR ProteomicsDB; 53875; -. [P21554-1] DR ProteomicsDB; 53876; -. [P21554-2] DR ProteomicsDB; 53877; -. [P21554-3] DR ABCD; P21554; 62 sequenced antibodies. DR Antibodypedia; 3355; 718 antibodies from 42 providers. DR DNASU; 1268; -. DR Ensembl; ENST00000369499.3; ENSP00000358511.2; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000369501.3; ENSP00000358513.2; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000428600.3; ENSP00000412192.2; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000468898.2; ENSP00000420188.1; ENSG00000118432.14. [P21554-3] DR Ensembl; ENST00000549890.2; ENSP00000446819.1; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000551417.2; ENSP00000446702.2; ENSG00000118432.14. [P21554-1] DR GeneID; 1268; -. DR KEGG; hsa:1268; -. DR MANE-Select; ENST00000369501.3; ENSP00000358513.2; NM_016083.6; NP_057167.2. DR AGR; HGNC:2159; -. DR ClinPGx; PA26681; -. DR CTD; 1268; -. DR DisGeNET; 1268; -. DR GeneCards; CNR1; -. DR HGNC; HGNC:2159; CNR1. DR HPA; ENSG00000118432; Tissue enhanced (adipose tissue, pituitary gland). DR MIM; 114610; gene. DR MIM; 601665; phenotype. DR OpenTargets; ENSG00000118432; -. DR VEuPathDB; HostDB:ENSG00000118432; -. DR eggNOG; KOG3656; Eukaryota. DR GeneTree; ENSGT01140000282530; -. DR HOGENOM; CLU_009579_7_0_1; -. DR InParanoid; P21554; -. DR OMA; HKHANSA; -. DR OrthoDB; 5966748at2759; -. DR PAN-GO; P21554; 6 GO annotations based on evolutionary models. DR PhylomeDB; P21554; -. DR PathwayCommons; P21554; -. DR Reactome; R-HSA-373076; Class A/1 (Rhodopsin-like receptors). DR Reactome; R-HSA-418594; G alpha (i) signalling events. DR SignaLink; P21554; -. DR SIGNOR; P21554; -. DR Agora; ENSG00000118432; -. DR BioGRID-ORCS; 1268; 19 hits in 1157 CRISPR screens. DR ChiTaRS; CNR1; human. DR EvolutionaryTrace; P21554; -. DR GeneWiki; Cannabinoid_receptor_type_1; -. DR GenomeRNAi; 1268; -. DR Pharos; P21554; Tclin. DR PRO; PR:P21554; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; P21554; protein. DR Bgee; ENSG00000118432; Expressed in ganglionic eminence and 150 other cell types or tissues. DR ExpressionAtlas; P21554; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0098982; C:GABA-ergic synapse; IEA:Ensembl. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0030426; C:growth cone; IEA:Ensembl. DR GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell. DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl. DR GO; GO:0004949; F:cannabinoid receptor activity; IDA:UniProtKB. DR GO; GO:0004930; F:G protein-coupled receptor activity; IBA:GO_Central. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IBA:GO_Central. DR GO; GO:0007188; P:adenylate cyclase-modulating G protein-coupled receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0007413; P:axonal fasciculation; IEA:Ensembl. DR GO; GO:0038171; P:cannabinoid signaling pathway; IDA:UniProtKB. DR GO; GO:0007187; P:G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; TAS:ProtInc. DR GO; GO:0042593; P:glucose homeostasis; IEA:Ensembl. DR GO; GO:0099509; P:regulation of presynaptic cytosolic calcium ion concentration; IEA:Ensembl. DR GO; GO:0098921; P:retrograde trans-synaptic signaling by endocannabinoid; IEA:Ensembl. DR CDD; cd15340; 7tmA_CB1; 1. DR FunFam; 1.20.1070.10:FF:000072; Cannabinoid receptor 1; 1. DR Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1. DR InterPro; IPR000810; Canbinoid_rcpt_1. DR InterPro; IPR002230; Cnbnoid_rcpt. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR PANTHER; PTHR22750; G-PROTEIN COUPLED RECEPTOR; 1. DR Pfam; PF00001; 7tm_1; 1. DR PIRSF; PIRSF037995; Cnoid_rcpt_1; 1. DR PRINTS; PR00522; CANABINOID1R. DR PRINTS; PR00362; CANNABINOIDR. DR PRINTS; PR00237; GPCRRHODOPSN. DR SMART; SM01381; 7TM_GPCR_Srsx; 1. DR SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1. DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cell projection; KW G-protein coupled receptor; Glycoprotein; Lipoprotein; Membrane; KW Mitochondrion; Mitochondrion outer membrane; Neurodegeneration; Obesity; KW Palmitate; Phosphoprotein; Proteomics identification; Receptor; KW Reference proteome; Synapse; Transducer; Transmembrane; KW Transmembrane helix. FT CHAIN 1..472 FT /note="Cannabinoid receptor 1" FT /id="PRO_0000069314" FT TOPO_DOM 1..116 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 117..142 FT /note="Helical; Name=1" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 143..154 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 155..175 FT /note="Helical; Name=2" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 176..187 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 188..212 FT /note="Helical; Name=3" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 213..232 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 233..255 FT /note="Helical; Name=4" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 256..273 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 274..299 FT /note="Helical; Name=5" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 300..344 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 345..365 FT /note="Helical; Name=6" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 366..377 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 378..399 FT /note="Helical; Name=7" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 400..472 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT REGION 2..23 FT /note="Required for mitochondrial localization" FT /evidence="ECO:0000250|UniProtKB:P47746" FT MOD_RES 425 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P47746" FT MOD_RES 429 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P47746" FT LIPID 415 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:21895628" FT CARBOHYD 77 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 83 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 1..89 FT /note="MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTS FT FRGSPFQEKMTAGDNPQLVPADQVNITEFYNKSLSSF -> MALQIPPSAPSPLTSCTW FT AQMTFSTKTS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7876112" FT /id="VSP_001868" FT VAR_SEQ 22..54 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15620723" FT /id="VSP_016529" FT MUTAGEN 155 FT /note="F->V: Enhanced G(i) signaling activation ability." FT /evidence="ECO:0000269|PubMed:35637350" FT MUTAGEN 155 FT /note="F->W: Reduced agonist-induced receptor activation." FT /evidence="ECO:0000269|PubMed:35637350" FT MUTAGEN 210 FT /note="T->A: 7-fold lower affinity for a synthetic agonist, FT CP55940, possibly due the stabilization of an inactive FT conformation." FT /evidence="ECO:0000269|PubMed:27851727" FT MUTAGEN 341..342 FT /note="LA->AL: Loss of activity, when assayed for GNAI1 FT GTPase stimulatory activity." FT /evidence="ECO:0000269|PubMed:12237474" FT MUTAGEN 415 FT /note="C->A: Loss of palmitoylation, marked loss of FT association with lipid rafts on the plasma membrane and FT loss of activity, when assayed for downstream GTP-binding FT and reduction in cAMP levels." FT /evidence="ECO:0000269|PubMed:21895628" FT CONFLICT 94 FT /note="E -> G (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 103 FT /note="M -> I (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 149 FT /note="C -> R (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 200 FT /note="F -> L (in Ref. 5; AAD34320)" FT /evidence="ECO:0000305" FT CONFLICT 216 FT /note="I -> V (in Ref. 5; AAD34320)" FT /evidence="ECO:0000305" FT CONFLICT 246 FT /note="V -> A (in Ref. 5; AAD34320)" FT /evidence="ECO:0000305" FT CONFLICT 298 FT /note="L -> P (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 332 FT /note="P -> S (in Ref. 12; AAI00972)" FT /evidence="ECO:0000305" FT STRAND 100..102 FT /evidence="ECO:0007829|PDB:7FEE" FT HELIX 105..107 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 113..143 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 145..148 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 151..153 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 154..178 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 186..219 FT /evidence="ECO:0007829|PDB:5U09" FT TURN 221..223 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 224..227 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 230..249 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 250..253 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 257..260 FT /evidence="ECO:0007829|PDB:5U09" FT STRAND 266..268 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 273..300 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 302..305 FT /evidence="ECO:0007829|PDB:6KPG" FT HELIX 306..309 FT /evidence="ECO:0007829|PDB:8K8J" FT HELIX 334..367 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 375..400 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 402..409 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 411..415 FT /evidence="ECO:0007829|PDB:2B0Y" SQ SEQUENCE 472 AA; 52858 MW; 1D2E49061D12ABF2 CRC64; MKSILDGLAD TTFRTITTDL LYVGSNDIQY EDIKGDMASK LGYFPQKFPL TSFRGSPFQE KMTAGDNPQL VPADQVNITE FYNKSLSSFK ENEENIQCGE NFMDIECFMV LNPSQQLAIA VLSLTLGTFT VLENLLVLCV ILHSRSLRCR PSYHFIGSLA VADLLGSVIF VYSFIDFHVF HRKDSRNVFL FKLGGVTASF TASVGSLFLT AIDRYISIHR PLAYKRIVTR PKAVVAFCLM WTIAIVIAVL PLLGWNCEKL QSVCSDIFPH IDETYLMFWI GVTSVLLLFI VYAYMYILWK AHSHAVRMIQ RGTQKSIIIH TSEDGKVQVT RPDQARMDIR LAKTLVLILV VLIICWGPLL AIMVYDVFGK MNKLIKTVFA FCSMLCLLNS TVNPIIYALR SKDLRHAFRS MFPSCEGTAQ PLDNSMGDSD CLHKHANNAA SVHRAAESCI KSTVKIAKVT MSVSTDTSAE AL // 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 FMT_HUMAN Reviewed; 389 AA. AC Q96DP5; B7Z734; DT 27-JAN-2003, integrated into UniProtKB/Swiss-Prot. DT 27-JAN-2003, sequence version 2. DT 28-JAN-2026, entry version 188. DE RecName: Full=Methionyl-tRNA formyltransferase, mitochondrial; DE Short=MtFMT; DE EC=2.1.2.9 {ECO:0000269|PubMed:21907147, ECO:0000269|PubMed:25288793}; DE Flags: Precursor; GN Name=MTFMT; Synonyms=FMT, FMT1; 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 [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE SEQUENCE RP [LARGE SCALE MRNA] OF 11-389 (ISOFORM 1). RC TISSUE=Neuroblastoma, and Synovium; 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 [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16572171; DOI=10.1038/nature04601; RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S., RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.; RT "Analysis of the DNA sequence and duplication history of human chromosome RT 15."; RL Nature 440:671-675(2006). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain, and Mammary gland; 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 [4] RP VARIANTS COXPD15 LEU-125 AND LEU-209, FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=21907147; DOI=10.1016/j.cmet.2011.07.010; RA Tucker E.J., Hershman S.G., Koehrer C., Belcher-Timme C.A., Patel J., RA Goldberger O.A., Christodoulou J., Silberstein J.M., McKenzie M., RA Ryan M.T., Compton A.G., Jaffe J.D., Carr S.A., Calvo S.E., RA RajBhandary U.L., Thorburn D.R., Mootha V.K.; RT "Mutations in MTFMT underlie a human disorder of formylation causing RT impaired mitochondrial translation."; RL Cell Metab. 14:428-434(2011). RN [5] RP VARIANTS MC1DN27 LEU-209 AND 332-ARG--GLU-389 DEL. RX PubMed=22499348; DOI=10.1136/jmedgenet-2012-100846; RA Haack T.B., Haberberger B., Frisch E.M., Wieland T., Iuso A., Gorza M., RA Strecker V., Graf E., Mayr J.A., Herberg U., Hennermann J.B., Klopstock T., RA Kuhn K.A., Ahting U., Sperl W., Wilichowski E., Hoffmann G.F., Tesarova M., RA Hansikova H., Zeman J., Plecko B., Zeviani M., Wittig I., Strom T.M., RA Schuelke M., Freisinger P., Meitinger T., Prokisch H.; RT "Molecular diagnosis in mitochondrial complex I deficiency using exome RT sequencing."; RL J. Med. Genet. 49:277-283(2012). RN [6] RP CHARACTERIZATION OF VARIANTS COXPD15 LEU-125 AND LEU-209, FUNCTION, AND RP CATALYTIC ACTIVITY. RX PubMed=25288793; DOI=10.1074/jbc.m114.610626; RA Sinha A., Koehrer C., Weber M.H., Masuda I., Mootha V.K., Hou Y.M., RA RajBhandary U.L.; RT "Biochemical characterization of pathogenic mutations in human RT mitochondrial methionyl-tRNA formyltransferase."; RL J. Biol. Chem. 289:32729-32741(2014). CC -!- FUNCTION: Methionyl-tRNA formyltransferase that formylates methionyl- CC tRNA in mitochondria and is crucial for translation initiation. CC {ECO:0000269|PubMed:21907147, ECO:0000269|PubMed:25288793}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-methionyl-tRNA(fMet) + (6R)-10-formyltetrahydrofolate = N- CC formyl-L-methionyl-tRNA(fMet) + (6S)-5,6,7,8-tetrahydrofolate + H(+); CC Xref=Rhea:RHEA:24380, Rhea:RHEA-COMP:9952, Rhea:RHEA-COMP:9953, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57453, ChEBI:CHEBI:78530, CC ChEBI:CHEBI:78844, ChEBI:CHEBI:195366; EC=2.1.2.9; CC Evidence={ECO:0000269|PubMed:25288793}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:24381; CC Evidence={ECO:0000269|PubMed:21907147}; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:O77480}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q96DP5-1; Sequence=Displayed; CC Name=2; CC IsoId=Q96DP5-2; Sequence=VSP_057059, VSP_057060; CC -!- DOMAIN: Composed of an N- and a C-terminal domain. The N-terminal CC domain carries the tetrahydrofolate (THF)-binding site and the C- CC terminal domain is presumably involved in positioning the Met-tRNA CC substrate for the formylation reaction. CC -!- DISEASE: Combined oxidative phosphorylation deficiency 15 (COXPD15) CC [MIM:614947]: An autosomal recessive, mitochondrial, neurologic CC disorder characterized by features of Leigh syndrome and combined CC oxidative phosphorylation deficiency. Clinical features include mild CC global developmental delay, white matter abnormalities, ataxia, CC incoordination, speech and reading difficulties, T2-weighted CC hyperintensities in the basal ganglia, corpus callosum, and brainstem. CC {ECO:0000269|PubMed:21907147, ECO:0000269|PubMed:25288793}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Mitochondrial complex I deficiency, nuclear type 27 (MC1DN27) CC [MIM:618248]: A form of mitochondrial complex I deficiency, the most CC common biochemical signature of mitochondrial disorders, a group of CC highly heterogeneous conditions characterized by defective oxidative CC phosphorylation, which collectively affects 1 in 5-10000 live births. CC Clinical disorders have variable severity, ranging from lethal neonatal CC disease to adult-onset neurodegenerative disorders. Phenotypes include CC macrocephaly with progressive leukodystrophy, non-specific CC encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh CC syndrome, Leber hereditary optic neuropathy, and some forms of CC Parkinson disease. MC1DN27 transmission pattern is consistent with CC autosomal recessive inheritance. {ECO:0000269|PubMed:22499348}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the Fmt family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH16630.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH33687.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAB70984.1; Type=Erroneous initiation; Note=Truncated N-terminus.; 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; AK055688; BAB70984.1; ALT_INIT; mRNA. DR EMBL; AK301390; BAH13470.1; -; mRNA. DR EMBL; AC013553; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC103691; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC016630; AAH16630.2; ALT_INIT; mRNA. DR EMBL; BC033687; AAH33687.1; ALT_INIT; mRNA. DR CCDS; CCDS45280.1; -. [Q96DP5-1] DR RefSeq; NP_640335.2; NM_139242.4. [Q96DP5-1] DR AlphaFoldDB; Q96DP5; -. DR SMR; Q96DP5; -. DR BioGRID; 125820; 98. DR FunCoup; Q96DP5; 640. DR IntAct; Q96DP5; 9. DR STRING; 9606.ENSP00000220058; -. DR DrugBank; DB00116; Tetrahydrofolic acid. DR iPTMnet; Q96DP5; -. DR PhosphoSitePlus; Q96DP5; -. DR BioMuta; MTFMT; -. DR DMDM; 27923776; -. DR jPOST; Q96DP5; -. DR MassIVE; Q96DP5; -. DR PaxDb; 9606-ENSP00000220058; -. DR PeptideAtlas; Q96DP5; -. DR ProteomicsDB; 6828; -. DR ProteomicsDB; 76304; -. [Q96DP5-1] DR Pumba; Q96DP5; -. DR Antibodypedia; 25895; 174 antibodies from 15 providers. DR DNASU; 123263; -. DR Ensembl; ENST00000220058.9; ENSP00000220058.4; ENSG00000103707.11. [Q96DP5-1] DR Ensembl; ENST00000543678.1; ENSP00000443754.1; ENSG00000103707.11. [Q96DP5-2] DR Ensembl; ENST00000558460.5; ENSP00000452646.1; ENSG00000103707.11. [Q96DP5-1] DR GeneID; 123263; -. DR KEGG; hsa:123263; -. DR MANE-Select; ENST00000220058.9; ENSP00000220058.4; NM_139242.4; NP_640335.2. DR UCSC; uc002aof.5; human. [Q96DP5-1] DR AGR; HGNC:29666; -. DR ClinPGx; PA142671304; -. DR CTD; 123263; -. DR DisGeNET; 123263; -. DR GeneCards; MTFMT; -. DR GeneReviews; MTFMT; -. DR HGNC; HGNC:29666; MTFMT. DR HPA; ENSG00000103707; Low tissue specificity. DR MalaCards; MTFMT; -. DR MIM; 611766; gene. DR MIM; 614947; phenotype. DR MIM; 618248; phenotype. DR OpenTargets; ENSG00000103707; -. DR Orphanet; 319524; Combined oxidative phosphorylation defect type 15. DR VEuPathDB; HostDB:ENSG00000103707; -. DR eggNOG; KOG3082; Eukaryota. DR GeneTree; ENSGT00390000017828; -. DR HOGENOM; CLU_033347_0_0_1; -. DR InParanoid; Q96DP5; -. DR OMA; GASPIHE; -. DR OrthoDB; 10268103at2759; -. DR PAN-GO; Q96DP5; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q96DP5; -. DR BRENDA; 2.1.2.9; 2681. DR PathwayCommons; Q96DP5; -. DR Reactome; R-HSA-5368286; Mitochondrial translation initiation. DR SignaLink; Q96DP5; -. DR Agora; ENSG00000103707; -. DR BioGRID-ORCS; 123263; 154 hits in 1156 CRISPR screens. DR ChiTaRS; MTFMT; human. DR GeneWiki; MTFMT; -. DR GenomeRNAi; 123263; -. DR Pharos; Q96DP5; Tbio. DR PRO; PR:Q96DP5; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; Q96DP5; protein. DR Bgee; ENSG00000103707; Expressed in left ventricle myocardium and 169 other cell types or tissues. DR ExpressionAtlas; Q96DP5; baseline and differential. DR GO; GO:0005739; C:mitochondrion; HTP:FlyBase. DR GO; GO:0004479; F:methionyl-tRNA formyltransferase activity; IDA:UniProtKB. DR GO; GO:0071951; P:conversion of methionyl-tRNA to N-formyl-methionyl-tRNA; IDA:UniProtKB. DR CDD; cd08646; FMT_core_Met-tRNA-FMT_N; 1. DR FunFam; 3.40.50.12230:FF:000003; methionyl-tRNA formyltransferase, mitochondrial; 1. DR Gene3D; 3.40.50.12230; -; 1. DR InterPro; IPR005794; Fmt. DR InterPro; IPR005793; Formyl_trans_C. DR InterPro; IPR002376; Formyl_transf_N. DR InterPro; IPR036477; Formyl_transf_N_sf. DR InterPro; IPR011034; Formyl_transferase-like_C_sf. DR InterPro; IPR041711; Met-tRNA-FMT_N. DR NCBIfam; TIGR00460; fmt; 1. DR PANTHER; PTHR11138; METHIONYL-TRNA FORMYLTRANSFERASE; 1. DR PANTHER; PTHR11138:SF5; METHIONYL-TRNA FORMYLTRANSFERASE, MITOCHONDRIAL; 1. DR Pfam; PF02911; Formyl_trans_C; 1. DR Pfam; PF00551; Formyl_trans_N; 1. DR SUPFAM; SSF50486; FMT C-terminal domain-like; 1. DR SUPFAM; SSF53328; Formyltransferase; 1. PE 1: Evidence at protein level; KW Alternative splicing; Disease variant; Mitochondrion; KW Primary mitochondrial disease; Protein biosynthesis; KW Proteomics identification; Reference proteome; Transferase; KW Transit peptide. FT TRANSIT 1..? FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN ?..389 FT /note="Methionyl-tRNA formyltransferase, mitochondrial" FT /id="PRO_0000010093" FT VAR_SEQ 141..144 FT /note="GILN -> SFQF (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_057059" FT VAR_SEQ 145..389 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_057060" FT VARIANT 5 FT /note="V -> A (in dbSNP:rs2946655)" FT /id="VAR_059289" FT VARIANT 125 FT /note="S -> L (in COXPD15; loss of methionyl-tRNA FT formyltransferase activity; dbSNP:rs397514614)" FT /evidence="ECO:0000269|PubMed:21907147, FT ECO:0000269|PubMed:25288793" FT /id="VAR_069303" FT VARIANT 209 FT /note="S -> L (in COXPD15 and MC1DN27; decreased methionyl- FT tRNA formyltransferase activity; dbSNP:rs201431517)" FT /evidence="ECO:0000269|PubMed:21907147, FT ECO:0000269|PubMed:22499348, ECO:0000269|PubMed:25288793" FT /id="VAR_069304" FT VARIANT 332..389 FT /note="Missing (in MC1DN27)" FT /evidence="ECO:0000269|PubMed:22499348" FT /id="VAR_081461" SQ SEQUENCE 389 AA; 43832 MW; EBBE92142AB954E0 CRC64; MRVLVRRCWG PPLAHGARRG RPSPQWRALA RLGWEDCRDS RVREKPPWRV LFFGTDQFAR EALRALHAAR ENKEEELIDK LEVVTMPSPS PKGLPVKQYA VQSQLPVYEW PDVGSGEYDV GVVASFGRLL NEALILKFPY GILNVHPSCL PRWRGPAPVI HTVLHGDTVT GVTIMQIRPK RFDVGPILKQ ETVPVPPKST AKELEAVLSR LGANMLISVL KNLPESLSNG RQQPMEGATY APKISAGTSC IKWEEQTSEQ IFRLYRAIGN IIPLQTLWMA NTIKLLDLVE VNSSVLADPK LTGQALIPGS VIYHKQSQIL LVYCKDGWIG VRSVMLKKSL TATDFYNGYL HPWYQKNSQA QPSQCRFQTL RLPTKKKQKK TVAMQQCIE // ID NDUA9_HUMAN Reviewed; 377 AA. AC Q16795; Q14076; Q2NKX0; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1997, sequence version 2. DT 28-JAN-2026, entry version 208. DE RecName: Full=NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial; DE AltName: Full=Complex I-39kD; DE Short=CI-39kD; DE AltName: Full=NADH-ubiquinone oxidoreductase 39 kDa subunit; DE Flags: Precursor; GN Name=NDUFA9; Synonyms=NDUFS2L; 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]. RA Loeffen J.L.C.M., Smeets R.J.P., Triepels R., Ruitenbeek W., RA Smeitink J.A.M., van den Heuvel L.; RT "39 kDa subunit of NADH-ubiquinone oxidoreductase."; RL Submitted (FEB-1998) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Colon, Muscle, and Skeletal muscle; 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 [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33. RC TISSUE=Blood; RX PubMed=8012384; DOI=10.1038/ng0394-236; RA Cross S.H., Charlton J.A., Nan X., Bird A.P.; RT "Purification of CpG islands using a methylated DNA binding column."; RL Nat. Genet. 6:236-244(1994). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 3-377. RC TISSUE=Liver; RX PubMed=8486360; DOI=10.1006/geno.1993.1161; RA Baens M., Chaffanet M., Cassiman J.-J., van den Berghe H., Marynen P.; RT "Construction and evaluation of a hncDNA library of human 12p transcribed RT sequences derived from a somatic cell hybrid."; RL Genomics 16:214-218(1993). RN [5] RP IDENTIFICATION IN THE NADH-UBIQUINONE OXIDOREDUCTASE COMPLEX, RP IDENTIFICATION BY MASS SPECTROMETRY, AND SUBCELLULAR LOCATION. RX PubMed=12611891; DOI=10.1074/jbc.c300064200; RA Murray J., Zhang B., Taylor S.W., Oglesbee D., Fahy E., Marusich M.F., RA Ghosh S.S., Capaldi R.A.; RT "The subunit composition of the human NADH dehydrogenase obtained by rapid RT one-step immunopurification."; RL J. Biol. Chem. 278:13619-13622(2003). RN [6] 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 [7] RP INTERACTION WITH BLOC1S1, AND ACETYLATION. RX PubMed=22309213; DOI=10.1042/bj20120118; RA Scott I., Webster B.R., Li J.H., Sack M.N.; RT "Identification of a molecular component of the mitochondrial acetyl RT transferase program; a novel role for GCN5L1."; RL Biochem. J. 443:655-661(2012). RN [8] 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 [9] 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 [10] RP FUNCTION, AND IDENTIFICATION IN THE NADH-UBIQUINONE OXIDOREDUCTASE COMPLEX. RX PubMed=27626371; DOI=10.1038/nature19754; RA Stroud D.A., Surgenor E.E., Formosa L.E., Reljic B., Frazier A.E., RA Dibley M.G., Osellame L.D., Stait T., Beilharz T.H., Thorburn D.R., RA Salim A., Ryan M.T.; RT "Accessory subunits are integral for assembly and function of human RT mitochondrial complex I."; RL Nature 538:123-126(2016). RN [11] RP INVOLVEMENT IN MC1DN26, VARIANT MC1DN26 PRO-321, AND FUNCTION. RX PubMed=22114105; DOI=10.1136/jmedgenet-2011-100466; RA van den Bosch B.J., Gerards M., Sluiter W., Stegmann A.P., Jongen E.L., RA Hellebrekers D.M., Oegema R., Lambrichs E.H., Prokisch H., Danhauser K., RA Schoonderwoerd K., de Coo I.F., Smeets H.J.; RT "Defective NDUFA9 as a novel cause of neonatally fatal complex I disease."; RL J. Med. Genet. 49:10-15(2012). RN [12] RP ACETYLATION, AND INTERACTION WITH CLOCK. RX PubMed=28985504; DOI=10.1016/j.molcel.2017.09.008; RA Lin R., Mo Y., Zha H., Qu Z., Xie P., Zhu Z.J., Xu Y., Xiong Y., Guan K.L.; RT "CLOCK acetylates ASS1 to drive circadian rhythm of ureagenesis."; RL Mol. Cell 68:198-209(2017). RN [13] RP FUNCTION, INVOLVEMENT IN MC1DN26, VARIANTS MC1DN26 PRO-321 AND CYS-360, AND RP CHARACTERIZATION OF VARIANTS MC1DN26 PRO-321 AND CYS-360. RX PubMed=28671271; DOI=10.1111/cge.13089; RA Baertling F., Sanchez-Caballero L., van den Brand M.A.M., Fung C.W., RA Chan S.H., Wong V.C., Hellebrekers D.M.E., de Coo I.F.M., Smeitink J.A.M., RA Rodenburg R.J.T., Nijtmans L.G.J.; RT "NDUFA9 point mutations cause a variable mitochondrial complex I assembly RT defect."; RL Clin. Genet. 93:111-118(2018). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY, AND INTERACTION WITH RAB5IF. RX PubMed=31536960; DOI=10.1016/j.isci.2019.08.057; RA Moutaoufik M.T., Malty R., Amin S., Zhang Q., Phanse S., Gagarinova A., RA Zilocchi M., Hoell L., Minic Z., Gagarinova M., Aoki H., Stockwell J., RA Jessulat M., Goebels F., Broderick K., Scott N.E., Vlasblom J., Musso G., RA Prasad B., Lamantea E., Garavaglia B., Rajput A., Murayama K., Okazaki Y., RA Foster L.J., Bader G.D., Cayabyab F.S., Babu M.; RT "Rewiring of the Human Mitochondrial Interactome during Neuronal RT Reprogramming Reveals Regulators of the Respirasome and Neurogenesis."; RL IScience 19:1114-1132(2019). CC -!- FUNCTION: Accessory subunit of the mitochondrial membrane respiratory CC chain NADH dehydrogenase (Complex I), that is believed not to be CC involved in catalysis. Required for proper complex I assembly CC (PubMed:28671271). Complex I functions in the transfer of electrons CC from NADH to the respiratory chain. The immediate electron acceptor for CC the enzyme is believed to be ubiquinone. {ECO:0000269|PubMed:22114105, CC ECO:0000269|PubMed:27626371, ECO:0000269|PubMed:28671271}. CC -!- COFACTOR: CC Name=FAD; Xref=ChEBI:CHEBI:57692; CC Note=Binds 1 FAD per subunit.; CC -!- SUBUNIT: Complex I is composed of 45 different subunits. This a CC component of the hydrophobic protein fraction (PubMed:12611891, CC PubMed:27626371). Interacts with BLOC1S1 (PubMed:22309213). Interacts CC with SLC2A4 (By similarity). Interacts with CLOCK (PubMed:28985504). CC Interacts with RAB5IF (PubMed:31536960). {ECO:0000250|UniProtKB:Q5BK63, CC ECO:0000269|PubMed:12611891, ECO:0000269|PubMed:22309213, CC ECO:0000269|PubMed:27626371, ECO:0000269|PubMed:28985504, CC ECO:0000269|PubMed:31536960}. CC -!- INTERACTION: CC Q16795; P78537: BLOC1S1; NbExp=3; IntAct=EBI-1045087, EBI-348630; CC Q16795; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-1045087, EBI-3867333; CC Q16795; P42858: HTT; NbExp=7; IntAct=EBI-1045087, EBI-466029; CC Q16795; Q3LI66: KRTAP6-2; NbExp=3; IntAct=EBI-1045087, EBI-11962084; CC Q16795; P28331: NDUFS1; NbExp=4; IntAct=EBI-1045087, EBI-1043922; CC Q16795; Q8NC60: NOA1; NbExp=2; IntAct=EBI-1045087, EBI-717871; CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix CC {ECO:0000305|PubMed:12611891}. CC -!- PTM: Acetylated on lysine residues. BLOC1S1 is required for acetylation CC (PubMed:22309213). Acetylated by CLOCK in a circadian manner CC (PubMed:28985504). {ECO:0000269|PubMed:22309213, CC ECO:0000269|PubMed:28985504}. CC -!- DISEASE: Mitochondrial complex I deficiency, nuclear type 26 (MC1DN26) CC [MIM:618247]: A form of mitochondrial complex I deficiency, the most CC common biochemical signature of mitochondrial disorders, a group of CC highly heterogeneous conditions characterized by defective oxidative CC phosphorylation, which collectively affects 1 in 5-10000 live births. CC Clinical disorders have variable severity, ranging from lethal neonatal CC disease to adult-onset neurodegenerative disorders. Phenotypes include CC macrocephaly with progressive leukodystrophy, non-specific CC encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh CC syndrome, Leber hereditary optic neuropathy, and some forms of CC Parkinson disease. MC1DN26 transmission pattern is consistent with CC autosomal recessive inheritance. {ECO:0000269|PubMed:22114105, CC ECO:0000269|PubMed:28671271}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the complex I NDUFA9 subunit family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=CAA54099.1; Type=Frameshift; 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; AF050641; AAD42055.1; -; mRNA. DR EMBL; BC009311; AAH09311.1; -; mRNA. DR EMBL; BC015837; AAH15837.1; -; mRNA. DR EMBL; BC111546; AAI11547.1; -; mRNA. DR EMBL; X76665; CAA54099.1; ALT_FRAME; Genomic_DNA. DR EMBL; L04490; AAA36350.1; -; mRNA. DR CCDS; CCDS8532.1; -. DR PIR; I37258; I37258. DR RefSeq; NP_004993.1; NM_005002.5. DR PDB; 5XTB; EM; 3.40 A; J=40-376. DR PDB; 5XTD; EM; 3.70 A; J=40-376. DR PDB; 5XTH; EM; 3.90 A; J=40-376. DR PDB; 5XTI; EM; 17.40 A; BJ/J=40-376. DR PDB; 9CWT; EM; 3.44 A; J=1-377. DR PDBsum; 5XTB; -. DR PDBsum; 5XTD; -. DR PDBsum; 5XTH; -. DR PDBsum; 5XTI; -. DR PDBsum; 9CWT; -. DR AlphaFoldDB; Q16795; -. DR EMDB; EMD-45974; -. DR SMR; Q16795; -. DR BioGRID; 110784; 358. DR ComplexPortal; CPX-577; Mitochondrial respiratory chain complex I. DR CORUM; Q16795; -. DR DIP; DIP-38526N; -. DR FunCoup; Q16795; 2517. DR IntAct; Q16795; 135. DR MINT; Q16795; -. DR STRING; 9606.ENSP00000266544; -. DR BindingDB; Q16795; -. DR ChEMBL; CHEMBL2363065; -. DR DrugBank; DB03147; Flavin adenine dinucleotide. DR DrugBank; DB00157; NADH. DR DrugCentral; Q16795; -. DR CarbonylDB; Q16795; -. DR GlyGen; Q16795; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q16795; -. DR PhosphoSitePlus; Q16795; -. DR SwissPalm; Q16795; -. DR BioMuta; NDUFA9; -. DR DMDM; 2833280; -. DR jPOST; Q16795; -. DR MassIVE; Q16795; -. DR PaxDb; 9606-ENSP00000266544; -. DR PeptideAtlas; Q16795; -. DR ProteomicsDB; 61072; -. DR Pumba; Q16795; -. DR TopDownProteomics; Q16795; -. DR Antibodypedia; 22301; 258 antibodies from 30 providers. DR DNASU; 4704; -. DR Ensembl; ENST00000266544.10; ENSP00000266544.5; ENSG00000139180.12. DR GeneID; 4704; -. DR KEGG; hsa:4704; -. DR MANE-Select; ENST00000266544.10; ENSP00000266544.5; NM_005002.5; NP_004993.1. DR UCSC; uc001qnc.4; human. DR AGR; HGNC:7693; -. DR ClinPGx; PA31499; -. DR CTD; 4704; -. DR DisGeNET; 4704; -. DR GeneCards; NDUFA9; -. DR HGNC; HGNC:7693; NDUFA9. DR HPA; ENSG00000139180; Low tissue specificity. DR MalaCards; NDUFA9; -. DR MIM; 603834; gene. DR MIM; 618247; phenotype. DR OpenTargets; ENSG00000139180; -. DR VEuPathDB; HostDB:ENSG00000139180; -. DR eggNOG; KOG2865; Eukaryota. DR GeneTree; ENSGT00390000006865; -. DR HOGENOM; CLU_007383_6_4_1; -. DR InParanoid; Q16795; -. DR OMA; PEDQFTN; -. DR OrthoDB; 275457at2759; -. DR PAN-GO; Q16795; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q16795; -. DR BioCyc; MetaCyc:HS06589-MONOMER; -. DR PathwayCommons; Q16795; -. DR Reactome; R-HSA-611105; Respiratory electron transport. DR Reactome; R-HSA-6799198; Complex I biogenesis. DR SignaLink; Q16795; -. DR SIGNOR; Q16795; -. DR Agora; ENSG00000139180; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 4704; 185 hits in 1172 CRISPR screens. DR CD-CODE; 91857CE7; Nucleolus. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; NDUFA9; human. DR GeneWiki; NDUFA9; -. DR GenomeRNAi; 4704; -. DR Pharos; Q16795; Tclin. DR PRO; PR:Q16795; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q16795; protein. DR Bgee; ENSG00000139180; Expressed in apex of heart and 205 other cell types or tissues. DR ExpressionAtlas; Q16795; baseline and differential. DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:ComplexPortal. DR GO; GO:0005759; C:mitochondrial matrix; IDA:UniProtKB. DR GO; GO:0031966; C:mitochondrial membrane; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; HTP:FlyBase. DR GO; GO:0005634; C:nucleus; HDA:UniProtKB. DR GO; GO:0045271; C:respiratory chain complex I; IDA:UniProtKB. DR GO; GO:0008137; F:NADH dehydrogenase (ubiquinone) activity; NAS:UniProtKB. DR GO; GO:0003954; F:NADH dehydrogenase activity; IMP:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IDA:MGI. DR GO; GO:0009060; P:aerobic respiration; NAS:ComplexPortal. DR GO; GO:0007623; P:circadian rhythm; IDA:UniProtKB. DR GO; GO:0006120; P:mitochondrial electron transport, NADH to ubiquinone; NAS:UniProtKB. DR GO; GO:0042776; P:proton motive force-driven mitochondrial ATP synthesis; NAS:ComplexPortal. DR GO; GO:0006814; P:sodium ion transport; NAS:UniProtKB. DR GO; GO:0006744; P:ubiquinone biosynthetic process; IBA:GO_Central. DR CDD; cd05271; NDUFA9_like_SDR_a; 1. DR FunFam; 3.40.50.720:FF:000246; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial; 1. DR Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1. DR InterPro; IPR051207; ComplexI_NDUFA9_subunit. DR InterPro; IPR001509; Epimerase_deHydtase. DR InterPro; IPR036291; NAD(P)-bd_dom_sf. DR PANTHER; PTHR12126:SF10; NADH DEHYDROGENASE [UBIQUINONE] 1 ALPHA SUBCOMPLEX SUBUNIT 9, MITOCHONDRIAL; 1. DR PANTHER; PTHR12126; NADH-UBIQUINONE OXIDOREDUCTASE 39 KDA SUBUNIT-RELATED; 1. DR Pfam; PF01370; Epimerase; 1. DR SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Disease variant; Electron transport; FAD; KW Flavoprotein; Mitochondrion; Primary mitochondrial disease; KW Proteomics identification; Reference proteome; Respiratory chain; KW Transit peptide; Transport. FT TRANSIT 1..35 FT /note="Mitochondrion" FT /evidence="ECO:0000250" FT CHAIN 36..377 FT /note="NADH dehydrogenase [ubiquinone] 1 alpha subcomplex FT subunit 9, mitochondrial" FT /id="PRO_0000019992" FT MOD_RES 175 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:Q9DC69" FT MOD_RES 189 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q9DC69" FT MOD_RES 370 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q9DC69" FT VARIANT 321 FT /note="R -> P (in MC1DN26; loss of function in complex I FT assembly; accumulation of several low and high molecular FT weight assembly intermediates is observed in patient FT fibroblasts; dbSNP:rs199592341)" FT /evidence="ECO:0000269|PubMed:22114105, FT ECO:0000269|PubMed:28671271" FT /id="VAR_078936" FT VARIANT 360 FT /note="R -> C (in MC1DN26; loss of function in complex I FT assembly; accumulation of several low and high molecular FT weight assembly intermediates is observed in patient FT fibroblasts; dbSNP:rs3210083)" FT /evidence="ECO:0000269|PubMed:28671271" FT /id="VAR_081457" FT STRAND 43..51 FT /evidence="ECO:0007829|PDB:5XTB" FT STRAND 55..57 FT /evidence="ECO:0007829|PDB:5XTB" FT TURN 59..62 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 64..75 FT /evidence="ECO:0007829|PDB:5XTB" FT STRAND 79..84 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 89..97 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 100..102 FT /evidence="ECO:0007829|PDB:5XTB" FT STRAND 103..107 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 114..119 FT /evidence="ECO:0007829|PDB:5XTB" FT TURN 120..122 FT /evidence="ECO:0007829|PDB:5XTB" FT STRAND 124..126 FT /evidence="ECO:0007829|PDB:5XTB" FT STRAND 137..139 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 141..144 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 147..159 FT /evidence="ECO:0007829|PDB:5XTB" FT STRAND 162..167 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 179..194 FT /evidence="ECO:0007829|PDB:5XTB" FT STRAND 199..201 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 212..223 FT /evidence="ECO:0007829|PDB:5XTB" FT STRAND 225..229 FT /evidence="ECO:0007829|PDB:5XTB" FT TURN 230..233 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 242..254 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 273..284 FT /evidence="ECO:0007829|PDB:5XTB" FT STRAND 290..293 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 295..305 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 316..323 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 335..337 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 345..347 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 349..353 FT /evidence="ECO:0007829|PDB:5XTB" FT TURN 354..356 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 359..362 FT /evidence="ECO:0007829|PDB:5XTB" FT HELIX 367..369 FT /evidence="ECO:0007829|PDB:5XTB" SQ SEQUENCE 377 AA; 42510 MW; 66A1CC7FCE86DD0E CRC64; MAAAAQSRVV RVLSMSRSAI TAIATSVCHG PPCRQLHHAL MPHGKGGRSS VSGIVATVFG ATGFLGRYVV NHLGRMGSQV IIPYRCDKYD IMHLRPMGDL GQLLFLEWDA RDKDSIRRVV QHSNVVINLI GRDWETKNFD FEDVFVKIPQ AIAQLSKEAG VEKFIHVSHL NANIKSSSRY LRNKAVGEKV VRDAFPEAII VKPSDIFGRE DRFLNSFASM HRFGPIPLGS LGWKTVKQPV YVVDVSKGIV NAVKDPDANG KSFAFVGPSR YLLFHLVKYI FAVAHRLFLP FPLPLFAYRW VARVFEISPF EPWITRDKVE RMHITDMKLP HLPGLEDLGI QATPLELKAI EVLRRHRTYR WLSAEIEDVK PAKTVNI // ID PDE8B_HUMAN Reviewed; 885 AA. AC O95263; Q5J7V7; Q86XK8; Q8IUJ7; Q8IUJ8; Q8IUJ9; Q8IUK0; Q8N3T2; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 22-AUG-2003, sequence version 2. DT 28-JAN-2026, entry version 215. DE RecName: Full=High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B; DE Short=HsPDE8B; DE EC=3.1.4.53 {ECO:0000269|PubMed:12681444}; DE AltName: Full=Cell proliferation-inducing gene 22 protein; GN Name=PDE8B; ORFNames=PIG22; 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] (ISOFORMS 1; 2 AND 6), AND TISSUE RP SPECIFICITY. RX PubMed=12372422; DOI=10.1016/s0006-291x(02)02371-9; RA Hayashi M., Shimada Y., Nishimura Y., Hama T., Tanaka T.; RT "Genomic organization, chromosomal localization, and alternative splicing RT of the human phosphodiesterase 8B gene."; RL Biochem. Biophys. Res. Commun. 297:1253-1258(2002). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4), CATALYTIC ACTIVITY, RP ACTIVITY REGULATION, AND TISSUE SPECIFICITY. RC TISSUE=Thyroid; RX PubMed=12681444; DOI=10.1016/s0898-6568(02)00146-8; RA Gamanuma M., Yuasa K., Sasaki T., Sakurai N., Kotera J., Omori K.; RT "Comparison of enzymatic characterization and gene organization of cyclic RT nucleotide phosphodiesterase 8 family in humans."; RL Cell. Signal. 15:565-574(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5). RA Kim J.W.; RT "Identification of a human proliferation-inducing gene."; RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases. 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=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 NUCLEOTIDE SEQUENCE [MRNA] OF 227-885 (ISOFORM 1). RX PubMed=9784418; DOI=10.1006/bbrc.1998.9379; RA Hayashi M., Matsushima K., Ohashi H., Tsunoda H., Murase S., Kawarada Y., RA Tanaka T.; RT "Molecular cloning and characterization of human PDE8B, a novel thyroid- RT specific isozyme of 3',5'-cyclic nucleotide phosphodiesterase."; RL Biochem. Biophys. Res. Commun. 250:751-756(1998). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 43-885 (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 [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-517, AND IDENTIFICATION BY RP 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 [9] RP INVOLVEMENT IN ADSD1. RX PubMed=20085714; DOI=10.1016/j.ajhg.2009.12.003; RA Appenzeller S., Schirmacher A., Halfter H., Baumer S., Pendziwiat M., RA Timmerman V., De Jonghe P., Fekete K., Stogbauer F., Ludemann P., Hund M., RA Quabius E.S., Ringelstein E.B., Kuhlenbaumer G.; RT "Autosomal-dominant striatal degeneration is caused by a mutation in the RT phosphodiesterase 8B gene."; RL Am. J. Hum. Genet. 86:83-87(2010). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-517, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-517, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; 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 [12] RP VARIANT PPNAD3 PRO-305, AND CHARACTERIZATION OF VARIANT PPNAD3 PRO-305. RX PubMed=18431404; DOI=10.1038/ejhg.2008.85; RA Horvath A., Giatzakis C., Tsang K., Greene E., Osorio P., Boikos S., RA Libe R., Patronas Y., Robinson-White A., Remmers E., Bertherat J., RA Nesterova M., Stratakis C.A.; RT "A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal RT hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B RT isoform in human adrenal cortex."; RL Eur. J. Hum. Genet. 16:1245-1253(2008). CC -!- FUNCTION: Hydrolyzes the second messenger cAMP, which is a key CC regulator of many important physiological processes. May be involved in CC specific signaling in the thyroid gland. CC -!- CATALYTIC ACTIVITY: CC Reaction=3',5'-cyclic AMP + H2O = AMP + H(+); Xref=Rhea:RHEA:25277, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:58165, CC ChEBI:CHEBI:456215; EC=3.1.4.53; CC Evidence={ECO:0000269|PubMed:12681444}; CC -!- COFACTOR: CC Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240; CC Evidence={ECO:0000250}; CC Note=Binds 2 divalent metal cations per subunit. Site 1 may CC preferentially bind zinc ions, while site 2 has a preference for CC magnesium and/or manganese ions. {ECO:0000250}; CC -!- ACTIVITY REGULATION: Inhibited by dipyridimole. Insensitive to CC selective PDE inhibitors including rolipram and milrinone as well as to CC the non-selective inhibitor, IBMX. Unaffected by cGMP. CC {ECO:0000269|PubMed:12681444}. CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic AMP degradation; AMP from CC 3',5'-cyclic AMP: step 1/1. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=1; Synonyms=PDE8B1; CC IsoId=O95263-1; Sequence=Displayed; CC Name=2; Synonyms=PDE8B2, PDE8B3; CC IsoId=O95263-2; Sequence=VSP_008084; CC Name=3; Synonyms=PDE8B3; CC IsoId=O95263-3; Sequence=VSP_008085; CC Name=4; Synonyms=PDE8B4; CC IsoId=O95263-4; Sequence=VSP_008082; CC Name=5; CC IsoId=O95263-5; Sequence=VSP_008081; CC Name=6; Synonyms=PDE8B2; CC IsoId=O95263-6; Sequence=VSP_008083; CC -!- TISSUE SPECIFICITY: Abundantly expressed in the thyroid. Also very CC weakly expressed in brain, spinal cord and placenta. In the thyroid CC isoform 1 predominates, and isoforms 2 and 6 are also highly expressed. CC In the placenta isoforms 1 and 2 are expressed equally. In the brain CC isoform 2 predominates. {ECO:0000269|PubMed:12372422, CC ECO:0000269|PubMed:12681444}. CC -!- DOMAIN: Composed of a C-terminal catalytic domain containing two CC putative divalent metal sites and an N-terminal regulatory domain. CC -!- DISEASE: Striatal degeneration, autosomal dominant 1 (ADSD1) CC [MIM:609161]: A movement disorder affecting the striatal part of the CC basal ganglia and characterized by bradykinesia, dysarthria and muscle CC rigidity. These symptoms resemble idiopathic Parkinson disease, but CC tremor is not present. {ECO:0000269|PubMed:20085714}. Note=The disease CC is caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Primary pigmented nodular adrenocortical disease 3 (PPNAD3) CC [MIM:614190]: A rare bilateral adrenal defect causing ACTH-independent CC Cushing syndrome. Macroscopic appearance of the adrenals is CC characteristic with small pigmented micronodules observed in the CC cortex. Adrenal glands show overall normal size and weight, and CC multiple small yellow-to-dark brown nodules surrounded by a cortex with CC a uniform appearance. Microscopically, there are moderate diffuse CC cortical hyperplasia with mostly nonpigmented nodules, multiple CC capsular deficits and massive circumscribed and infiltrating extra- CC adrenal cortical excrescences with micronodules. Clinical CC manifestations of Cushing syndrome include facial and truncal obesity, CC abdominal striae, muscular weakness, osteoporosis, arterial CC hypertension, diabetes. {ECO:0000269|PubMed:18431404}. Note=The disease CC is caused by variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 1]: Major isoform. CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family. CC PDE8 subfamily. {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; AY129948; AAN71723.1; -; mRNA. DR EMBL; AY129949; AAN71724.1; -; mRNA. DR EMBL; AY129950; AAN71725.1; -; Genomic_DNA. DR EMBL; AY129950; AAN71726.1; -; Genomic_DNA. DR EMBL; AY129950; AAN71727.1; -; Genomic_DNA. DR EMBL; AB085824; BAC53762.1; -; mRNA. DR EMBL; AB085825; BAC53763.1; -; mRNA. DR EMBL; AB085826; BAC53764.1; -; mRNA. DR EMBL; AB085827; BAC53765.1; -; mRNA. DR EMBL; AY423729; AAS00492.1; -; mRNA. DR EMBL; CH471084; EAW95803.1; -; Genomic_DNA. DR EMBL; BC043209; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AF079529; AAC69564.2; -; mRNA. DR EMBL; AL831924; CAD38584.1; -; mRNA. DR CCDS; CCDS34190.1; -. [O95263-3] DR CCDS; CCDS34191.1; -. [O95263-6] DR CCDS; CCDS34192.1; -. [O95263-2] DR CCDS; CCDS34193.1; -. [O95263-4] DR CCDS; CCDS4037.1; -. [O95263-1] DR PIR; JE0293; JE0293. DR RefSeq; NP_001025022.1; NM_001029851.4. [O95263-2] DR RefSeq; NP_001025023.1; NM_001029852.4. [O95263-3] DR RefSeq; NP_001025024.1; NM_001029853.4. [O95263-4] DR RefSeq; NP_001025025.1; NM_001029854.4. [O95263-6] DR RefSeq; NP_003710.1; NM_003719.5. [O95263-1] DR AlphaFoldDB; O95263; -. DR SMR; O95263; -. DR BioGRID; 114177; 12. DR CORUM; O95263; -. DR FunCoup; O95263; 217. DR IntAct; O95263; 4. DR MINT; O95263; -. DR STRING; 9606.ENSP00000264917; -. DR BindingDB; O95263; -. DR ChEMBL; CHEMBL4408; -. DR DrugBank; DB00201; Caffeine. DR DrugBank; DB09283; Trapidil. DR DrugCentral; O95263; -. DR GuidetoPHARMACOLOGY; 1308; -. DR iPTMnet; O95263; -. DR PhosphoSitePlus; O95263; -. DR BioMuta; PDE8B; -. DR jPOST; O95263; -. DR MassIVE; O95263; -. DR PaxDb; 9606-ENSP00000264917; -. DR PeptideAtlas; O95263; -. DR ProteomicsDB; 50759; -. [O95263-1] DR ProteomicsDB; 50760; -. [O95263-2] DR ProteomicsDB; 50761; -. [O95263-3] DR ProteomicsDB; 50762; -. [O95263-4] DR ProteomicsDB; 50763; -. [O95263-5] DR ProteomicsDB; 50764; -. [O95263-6] DR Pumba; O95263; -. DR Antibodypedia; 12495; 151 antibodies from 26 providers. DR DNASU; 8622; -. DR Ensembl; ENST00000264917.10; ENSP00000264917.6; ENSG00000113231.14. [O95263-1] DR Ensembl; ENST00000333194.8; ENSP00000331336.4; ENSG00000113231.14. [O95263-3] DR Ensembl; ENST00000340978.7; ENSP00000345446.3; ENSG00000113231.14. [O95263-6] DR Ensembl; ENST00000342343.8; ENSP00000345646.4; ENSG00000113231.14. [O95263-4] DR Ensembl; ENST00000346042.7; ENSP00000330428.3; ENSG00000113231.14. [O95263-2] DR Ensembl; ENST00000505283.1; ENSP00000423461.1; ENSG00000113231.14. [O95263-5] DR GeneID; 8622; -. DR KEGG; hsa:8622; -. DR MANE-Select; ENST00000264917.10; ENSP00000264917.6; NM_003719.5; NP_003710.1. DR UCSC; uc003kfa.4; human. [O95263-1] DR AGR; HGNC:8794; -. DR ClinPGx; PA33142; -. DR CTD; 8622; -. DR DisGeNET; 8622; -. DR GeneCards; PDE8B; -. DR HGNC; HGNC:8794; PDE8B. DR HPA; ENSG00000113231; Tissue enriched (thyroid). DR MalaCards; PDE8B; -. DR MIM; 603390; gene. DR MIM; 609161; phenotype. DR MIM; 614190; phenotype. DR OpenTargets; ENSG00000113231; -. DR Orphanet; 228169; Autosomal dominant striatal neurodegeneration. DR Orphanet; 647782; Isolated micronodular adrenocortical disease. DR VEuPathDB; HostDB:ENSG00000113231; -. DR eggNOG; KOG1229; Eukaryota. DR GeneTree; ENSGT00940000157817; -. DR HOGENOM; CLU_005940_4_2_1; -. DR InParanoid; O95263; -. DR OMA; RWCCGGS; -. DR OrthoDB; 189220at2759; -. DR PAN-GO; O95263; 2 GO annotations based on evolutionary models. DR PhylomeDB; O95263; -. DR BRENDA; 3.1.4.53; 2681. DR PathwayCommons; O95263; -. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR SignaLink; O95263; -. DR UniPathway; UPA00762; UER00747. DR Agora; ENSG00000113231; -. DR BioGRID-ORCS; 8622; 19 hits in 1161 CRISPR screens. DR ChiTaRS; PDE8B; human. DR GeneWiki; PDE8B; -. DR GenomeRNAi; 8622; -. DR Pharos; O95263; Tclin. DR PRO; PR:O95263; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; O95263; protein. DR Bgee; ENSG00000113231; Expressed in left lobe of thyroid gland and 104 other cell types or tissues. DR ExpressionAtlas; O95263; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0004115; F:3',5'-cyclic-AMP phosphodiesterase activity; IMP:UniProtKB. DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; IBA:GO_Central. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0001662; P:behavioral fear response; IEA:Ensembl. DR GO; GO:0006198; P:cAMP catabolic process; IEA:UniProtKB-UniPathway. DR GO; GO:0141162; P:negative regulation of cAMP/PKA signal transduction; IBA:GO_Central. DR GO; GO:0061179; P:negative regulation of insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0090032; P:negative regulation of steroid hormone biosynthetic process; IEA:Ensembl. DR GO; GO:0050885; P:neuromuscular process controlling balance; IEA:Ensembl. DR GO; GO:0035106; P:operant conditioning; IEA:Ensembl. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IBA:GO_Central. DR GO; GO:0007165; P:signal transduction; IEA:InterPro. DR GO; GO:0008542; P:visual learning; IEA:Ensembl. DR CDD; cd00077; HDc; 1. DR CDD; cd00130; PAS; 1. DR FunFam; 1.10.1300.10:FF:000002; Phosphodiesterase; 1. DR FunFam; 3.30.450.20:FF:000023; Phosphodiesterase; 1. DR Gene3D; 1.10.1300.10; 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain; 1. DR Gene3D; 3.30.450.20; PAS domain; 1. DR InterPro; IPR003607; HD/PDEase_dom. DR InterPro; IPR000014; PAS. DR InterPro; IPR035965; PAS-like_dom_sf. DR InterPro; IPR057304; PDE8-like_REC_N. DR InterPro; IPR023088; PDEase. DR InterPro; IPR002073; PDEase_catalytic_dom. DR InterPro; IPR036971; PDEase_catalytic_dom_sf. DR InterPro; IPR023174; PDEase_CS. DR NCBIfam; TIGR00229; sensory_box; 1. DR PANTHER; PTHR11347; CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; 1. DR Pfam; PF13426; PAS_9; 1. DR Pfam; PF08629; PDE8; 1. DR Pfam; PF23198; PDE8A_N; 1. DR Pfam; PF00233; PDEase_I; 1. DR PRINTS; PR00387; PDIESTERASE1. DR SMART; SM00471; HDc; 1. DR SMART; SM00091; PAS; 1. DR SUPFAM; SSF109604; HD-domain/PDEase-like; 1. DR SUPFAM; SSF55785; PYP-like sensor domain (PAS domain); 1. DR PROSITE; PS50112; PAS; 1. DR PROSITE; PS00126; PDEASE_I_1; 1. DR PROSITE; PS51845; PDEASE_I_2; 1. PE 1: Evidence at protein level; KW Alternative splicing; cAMP; Cushing syndrome; Disease variant; Hydrolase; KW Metal-binding; Phosphoprotein; Proteomics identification; KW Reference proteome. FT CHAIN 1..885 FT /note="High affinity cAMP-specific and IBMX-insensitive FT 3',5'-cyclic phosphodiesterase 8B" FT /id="PRO_0000198840" FT DOMAIN 267..338 FT /note="PAS" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 539..875 FT /note="PDEase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192" FT REGION 18..41 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 72..95 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 393..436 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 23..34 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 75..90 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 422..436 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 615 FT /note="Proton donor" FT /evidence="ECO:0000250|UniProtKB:O76083" FT BINDING 619 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:O60658" FT BINDING 655 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:O60658" FT BINDING 656 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:O60658" FT BINDING 656 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:O60658" FT BINDING 781 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:O60658" FT MOD_RES 517 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 754 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:E9Q4S1" FT VAR_SEQ 1..535 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.3" FT /id="VSP_008081" FT VAR_SEQ 114..133 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:12681444" FT /id="VSP_008082" FT VAR_SEQ 293..389 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:12372422, FT ECO:0000303|PubMed:12681444" FT /id="VSP_008084" FT VAR_SEQ 293..339 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|PubMed:12372422" FT /id="VSP_008083" FT VAR_SEQ 456..510 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:12681444" FT /id="VSP_008085" FT VARIANT 305 FT /note="H -> P (in PPNAD3; shows significantly higher cyclic FT AMP levels after transfection with the mutant protein than FT after transfection with the wild-type, indicating an FT impaired ability of the mutant protein to degrade cAMP; FT dbSNP:rs121918360)" FT /evidence="ECO:0000269|PubMed:18431404" FT /id="VAR_066503" FT CONFLICT 147 FT /note="G -> R (in Ref. 7; CAD38584)" FT /evidence="ECO:0000305" SQ SEQUENCE 885 AA; 98979 MW; DB4F763E51F745A3 CRC64; MGCAPSIHVS QSGVIYCRDS DESSSPRQTT SVSQGPAAPL PGLFVQTDAA DAIPPSRASG PPSVARVRRA RTELGSGSSA GSAAPAATTS RGRRRHCCSS AEAETQTCYT SVKQVSSAEV RIGPMRLTQD PIQVLLIFAK EDSQSDGFWW ACDRAGYRCN IARTPESALE CFLDKHHEII VIDHRQTQNF DAEAVCRSIR ATNPSEHTVI LAVVSRVSDD HEEASVLPLL HAGFNRRFME NSSIIACYNE LIQIEHGEVR SQFKLRACNS VFTALDHCHE AIEITSDDHV IQYVNPAFER MMGYHKGELL GKELADLPKS DKNRADLLDT INTCIKKGKE WQGVYYARRK SGDSIQQHVK ITPVIGQGGK IRHFVSLKKL CCTTDNNKQI HKIHRDSGDN SQTEPHSFRY KNRRKESIDV KSISSRGSDA PSLQNRRYPS MARIHSMTIE APITKVINII NAAQENSPVT VAEALDRVLE ILRTTELYSP QLGTKDEDPH TSDLVGGLMT DGLRRLSGNE YVFTKNVHQS HSHLAMPITI NDVPPCISQL LDNEESWDFN IFELEAITHK RPLVYLGLKV FSRFGVCEFL NCSETTLRAW FQVIEANYHS SNAYHNSTHA ADVLHATAFF LGKERVKGSL DQLDEVAALI AATVHDVDHP GRTNSFLCNA GSELAVLYND TAVLESHHTA LAFQLTVKDT KCNIFKNIDR NHYRTLRQAI IDMVLATEMT KHFEHVNKFV NSINKPMAAE IEGSDCECNP AGKNFPENQI LIKRMMIKCA DVANPCRPLD LCIEWAGRIS EEYFAQTDEE KRQGLPVVMP VFDRNTCSIP KSQISFIDYF ITDMFDAWDA FAHLPALMQH LADNYKHWKT LDDLKCKSLR LPSDS // ID QCR1_HUMAN Reviewed; 480 AA. AC P31930; B2R7R8; Q96DD2; DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot. DT 04-APR-2006, sequence version 3. DT 28-JAN-2026, entry version 228. DE RecName: Full=Cytochrome b-c1 complex subunit 1, mitochondrial; DE AltName: Full=Complex III subunit 1; DE AltName: Full=Core protein I; DE AltName: Full=Ubiquinol-cytochrome-c reductase complex core protein 1; DE Flags: Precursor; GN Name=UQCRC1; 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 VARIANT SER-301. RC TISSUE=Placenta; RX PubMed=8407948; DOI=10.1016/s0021-9258(19)36900-5; RA Hoffman G.G., Lee S., Christiano A.M., Chung-Honet L.C., Cheng W., RA Katchman S., Uitto J., Greenspan D.S.; RT "Complete coding sequence, intron/exon organization, and chromosomal RT location of the gene for the core I protein of human ubiquinol-cytochrome c RT reductase."; RL J. Biol. Chem. 268:21113-21119(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Fibroblast; RX PubMed=8069229; RA Islam M.M., Tanaka M., Suzuki H., Torii K., Hattori N., Ozawa T.; RT "A complete cDNA sequence for core I protein subunit of human ubiquinol- RT cytochrome c reductase."; RL Biochem. Mol. Biol. Int. 32:797-805(1994). RN [3] RP ERRATUM OF PUBMED:8069229. RX PubMed=7951059; RA Islam M.M., Tanaka M., Suzuki H., Torii K., Hattori N., Ozawa T.; RL Biochem. Mol. Biol. Int. 33:410-410(1994). RN [4] RP ERRATUM OF PUBMED:8069229. RX PubMed=7981668; RA Islam M.M., Tanaka M., Suzuki H., Torii K., Hattori N., Ozawa T.; RL Biochem. Mol. Biol. Int. 33:815-815(1994). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Subthalamic nucleus; 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 [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 [LARGE SCALE MRNA]. RC TISSUE=Bone marrow; 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 PROTEIN SEQUENCE OF 35-45. RC TISSUE=Liver; RX PubMed=8313870; DOI=10.1002/elps.11501401181; RA Hughes G.J., Frutiger S., Paquet N., Pasquali C., Sanchez J.-C., RA Tissot J.-D., Bairoch A., Appel R.D., Hochstrasser D.F.; RT "Human liver protein map: update 1993."; RL Electrophoresis 14:1216-1222(1993). RN [9] RP PROTEIN SEQUENCE OF 86-99; 214-225; 229-248; 397-415; 424-442; 448-470 AND RP 473-479, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex; RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [10] RP PROTEIN SEQUENCE OF 143-165; 181-209 AND 397-415. RC TISSUE=Adipocyte; RX PubMed=15242332; DOI=10.1042/bj20040647; RA Aboulaich N., Vainonen J.P., Stralfors P., Vener A.V.; RT "Vectorial proteomics reveal targeting, phosphorylation and specific RT fragmentation of polymerase I and transcript release factor (PTRF) at the RT surface of caveolae in human adipocytes."; RL Biochem. J. 383:237-248(2004). RN [11] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-111, AND IDENTIFICATION BY MASS RP 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 [12] 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 [13] 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 [14] RP CLEAVAGE OF TRANSIT PEPTIDE [LARGE SCALE ANALYSIS] AFTER SER-34, AND 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 [15] RP FUNCTION. RX PubMed=29243944; DOI=10.1080/15384101.2017.1417707; RA Fernandez-Vizarra E., Zeviani M.; RT "Mitochondrial complex III Rieske Fe-S protein processing and assembly."; RL Cell Cycle 17:681-687(2018). RN [16] RP INTERACTION WITH UQCC6. RX PubMed=32161263; DOI=10.1038/s41467-020-14999-2; RA Zhang S., Reljic B., Liang C., Kerouanton B., Francisco J.C., Peh J.H., RA Mary C., Jagannathan N.S., Olexiouk V., Tang C., Fidelito G., Nama S., RA Cheng R.K., Wee C.L., Wang L.C., Duek Roggli P., Sampath P., Lane L., RA Petretto E., Sobota R.M., Jesuthasan S., Tucker-Kellogg L., Reversade B., RA Menschaert G., Sun L., Stroud D.A., Ho L.; RT "Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory RT complex III assembly."; RL Nat. Commun. 11:1312-1312(2020). RN [17] RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), AND SUBUNIT. RX PubMed=28844695; DOI=10.1016/j.cell.2017.07.050; RA Guo R., Zong S., Wu M., Gu J., Yang M.; RT "Architecture of human mitochondrial respiratory megacomplex I2III2IV2."; RL Cell 170:1247-1257(2017). RN [18] RP VARIANT SER-301. RX PubMed=10453733; DOI=10.1007/s004390050988; RA Valnot I., Kassis J., Chretien D., de Lonlay P., Parfait B., Munnich A., RA Kachaner J., Rustin P., Roetig A.; RT "A mitochondrial cytochrome b mutation but no mutations of nuclearly RT encoded subunits in ubiquinol cytochrome c reductase (complex III) RT deficiency."; RL Hum. Genet. 104:460-466(1999). RN [19] RP INVOLVEMENT IN PKNPY, VARIANTS PKNPY LEU-311 AND SER-314, FUNCTION, AND RP TISSUE SPECIFICITY. RX PubMed=33141179; DOI=10.1093/brain/awaa279; RA Lin C.H., Tsai P.I., Lin H.Y., Hattori N., Funayama M., Jeon B., Sato K., RA Abe K., Mukai Y., Takahashi Y., Li Y., Nishioka K., Yoshino H., Daida K., RA Chen M.L., Cheng J., Huang C.Y., Tzeng S.R., Wu Y.S., Lai H.J., Tsai H.H., RA Yen R.F., Lee N.C., Lo W.C., Hung Y.C., Chan C.C., Ke Y.C., Chao C.C., RA Hsieh S.T., Farrer M., Wu R.M.; RT "Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with RT polyneuropathy."; RL Brain 143:3352-3373(2020). CC -!- FUNCTION: Component of the ubiquinol-cytochrome c oxidoreductase, a CC multisubunit transmembrane complex that is part of the mitochondrial CC electron transport chain which drives oxidative phosphorylation. The CC respiratory chain contains 3 multisubunit complexes succinate CC dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase CC (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase CC (complex IV, CIV), that cooperate to transfer electrons derived from CC NADH and succinate to molecular oxygen, creating an electrochemical CC gradient over the inner membrane that drives transmembrane transport CC and the ATP synthase. The cytochrome b-c1 complex catalyzes electron CC transfer from ubiquinol to cytochrome c, linking this redox reaction to CC translocation of protons across the mitochondrial inner membrane, with CC protons being carried across the membrane as hydrogens on the quinol. CC In the process called Q cycle, 2 protons are consumed from the matrix, CC 4 protons are released into the intermembrane space and 2 electrons are CC passed to cytochrome c (By similarity). The 2 core subunits UQCRC1/QCR1 CC and UQCRC2/QCR2 are homologous to the 2 mitochondrial-processing CC peptidase (MPP) subunits beta-MPP and alpha-MPP respectively, and they CC seem to have preserved their MPP processing properties (By similarity). CC May be involved in the in situ processing of UQCRFS1 into the mature CC Rieske protein and its mitochondrial targeting sequence (MTS)/subunit 9 CC when incorporated into complex III (Probable). Seems to play an CC important role in the maintenance of proper mitochondrial function in CC nigral dopaminergic neurons (PubMed:33141179). CC {ECO:0000250|UniProtKB:P07256, ECO:0000250|UniProtKB:P31800, CC ECO:0000269|PubMed:33141179, ECO:0000305|PubMed:29243944}. CC -!- SUBUNIT: Component of the ubiquinol-cytochrome c oxidoreductase CC (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme CC composed of 11 subunits. The complex is composed of 3 respiratory CC subunits cytochrome b, cytochrome c1 and Rieske protein UQCRFS1, 2 core CC protein subunits UQCRC1/QCR1 and UQCRC2/QCR2, and 6 low-molecular CC weight protein subunits UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, CC UQCR10/QCR9, UQCR11/QCR10 and subunit 9, the cleavage product of Rieske CC protein UQCRFS1 (By similarity). The complex exists as an obligatory CC dimer and forms supercomplexes (SCs) in the inner mitochondrial CC membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and CC cytochrome c oxidase (complex IV, CIV), resulting in different CC assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex CC MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with UQCC6 CC (PubMed:32161263). Interacts with STMP1 (By similarity). CC {ECO:0000250|UniProtKB:P31800, ECO:0000250|UniProtKB:Q9CZ13, CC ECO:0000269|PubMed:28844695, ECO:0000269|PubMed:32161263}. CC -!- INTERACTION: CC P31930; P52566: ARHGDIB; NbExp=3; IntAct=EBI-1052596, EBI-2806617; CC P31930; Q14457: BECN1; NbExp=3; IntAct=EBI-1052596, EBI-949378; CC P31930; Q9UFG5: C19orf25; NbExp=3; IntAct=EBI-1052596, EBI-741214; CC P31930; Q8WU43: C2orf15; NbExp=3; IntAct=EBI-1052596, EBI-12904676; CC P31930; Q8IV13: CCNJL; NbExp=3; IntAct=EBI-1052596, EBI-21668062; CC P31930; Q9Y6G5: COMMD10; NbExp=3; IntAct=EBI-1052596, EBI-1550310; CC P31930; P26641: EEF1G; NbExp=3; IntAct=EBI-1052596, EBI-351467; CC P31930; Q9UI10: EIF2B4; NbExp=3; IntAct=EBI-1052596, EBI-2340132; CC P31930; Q06547-2: GABPB1; NbExp=3; IntAct=EBI-1052596, EBI-618189; CC P31930; Q9HC44: GPBP1L1; NbExp=3; IntAct=EBI-1052596, EBI-746674; CC P31930; Q8N5Z5: KCTD17; NbExp=3; IntAct=EBI-1052596, EBI-743960; CC P31930; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-1052596, EBI-11985629; CC P31930; Q8N108-16: MIER1; NbExp=3; IntAct=EBI-1052596, EBI-25830642; CC P31930; C9J082: NPHP1; NbExp=3; IntAct=EBI-1052596, EBI-25830675; CC P31930; Q9UHV9: PFDN2; NbExp=3; IntAct=EBI-1052596, EBI-359873; CC P31930; Q00169: PITPNA; NbExp=3; IntAct=EBI-1052596, EBI-1042490; CC P31930; O14744: PRMT5; NbExp=3; IntAct=EBI-1052596, EBI-351098; CC P31930; O95416: SOX14; NbExp=3; IntAct=EBI-1052596, EBI-9087806; CC P31930; Q9BUA3: SPINDOC; NbExp=3; IntAct=EBI-1052596, EBI-1773488; CC P31930; O43704: SULT1B1; NbExp=3; IntAct=EBI-1052596, EBI-10179062; CC P31930; O95947: TBX6; NbExp=3; IntAct=EBI-1052596, EBI-2824328; CC P31930; Q8WTV1: THAP3; NbExp=3; IntAct=EBI-1052596, EBI-17438286; CC P31930; Q9BZM4: ULBP3; NbExp=3; IntAct=EBI-1052596, EBI-1032551; CC P31930; P22695: UQCRC2; NbExp=4; IntAct=EBI-1052596, EBI-1051424; CC P31930; Q6ZMY6-2: WDR88; NbExp=3; IntAct=EBI-1052596, EBI-25857007; CC P31930; Q9UNY5: ZNF232; NbExp=3; IntAct=EBI-1052596, EBI-749023; CC P31930; Q96MN9-2: ZNF488; NbExp=3; IntAct=EBI-1052596, EBI-25831733; CC P31930; Q8N8E2: ZNF513; NbExp=3; IntAct=EBI-1052596, EBI-10279993; CC P31930; Q9P0T4: ZNF581; NbExp=3; IntAct=EBI-1052596, EBI-745520; CC P31930; Q9BRT8: ZNG1A; NbExp=3; IntAct=EBI-1052596, EBI-1054417; CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane CC {ECO:0000250|UniProtKB:P07256}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:P07256}; Matrix side CC {ECO:0000250|UniProtKB:P07256}. CC -!- TISSUE SPECIFICITY: Expressed in brain, including substantia nigra, CC striatum, cortex and cerebellum, and in spinal cord, heart, kidney, CC liver and muscle. {ECO:0000269|PubMed:33141179}. CC -!- DISEASE: Parkinsonism with polyneuropathy (PKNPY) [MIM:619279]: An CC autosomal dominant disorder characterized by late-onset, levodopa- CC responsive parkinsonism with asymmetric tremor, rigidity and CC bradykinesia. Patients also manifest a sensorimotor polyneuropathy with CC variable degrees of distal legs and hands muscle atrophy and weakness, CC and absent deep tendon reflexes. {ECO:0000269|PubMed:33141179}. CC Note=The protein represented in this entry is involved in disease CC pathogenesis. CC -!- SIMILARITY: Belongs to the peptidase M16 family. UQCRC1/QCR1 subfamily. 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; L16842; AAA20046.1; -; mRNA. DR EMBL; D26485; BAA05495.1; -; mRNA. DR EMBL; AK313090; BAG35915.1; -; mRNA. DR EMBL; CH471055; EAW64898.1; -; Genomic_DNA. DR EMBL; BC009586; AAH09586.1; -; mRNA. DR CCDS; CCDS2774.1; -. DR PIR; A48043; A48043. DR RefSeq; NP_003356.2; NM_003365.2. DR RefSeq; XP_054203719.1; XM_054347744.1. DR PDB; 5XTE; EM; 3.40 A; L/Y=35-480. DR PDB; 5XTH; EM; 3.90 A; AL/AY=35-480. DR PDB; 5XTI; EM; 17.40 A; AL/AY=35-480. DR PDB; 9CG3; EM; 2.96 A; L/Y=1-480. DR PDBsum; 5XTE; -. DR PDBsum; 5XTH; -. DR PDBsum; 5XTI; -. DR PDBsum; 9CG3; -. DR AlphaFoldDB; P31930; -. DR EMDB; EMD-45567; -. DR SMR; P31930; -. DR BioGRID; 113230; 239. DR ComplexPortal; CPX-560; Mitochondrial respiratory chain complex III. DR FunCoup; P31930; 1647. DR IntAct; P31930; 113. DR MINT; P31930; -. DR STRING; 9606.ENSP00000203407; -. DR DrugBank; DB07763; (5S)-3-ANILINO-5-(2,4-DIFLUOROPHENYL)-5-METHYL-1,3-OXAZOLIDINE-2,4-DIONE. DR DrugBank; DB07778; (S)-famoxadone. DR DrugBank; DB04141; 2-Hexyloxy-6-Hydroxymethyl-Tetrahydro-Pyran-3,4,5-Triol. DR DrugBank; DB08453; 2-Nonyl-4-quinolinol 1-oxide. DR DrugBank; DB04799; 6-Hydroxy-5-undecyl-4,7-benzothiazoledione. DR DrugBank; DB07401; Azoxystrobin. DR DrugBank; DB08330; METHYL (2Z)-3-METHOXY-2-{2-[(E)-2-PHENYLVINYL]PHENYL}ACRYLATE. DR DrugBank; DB04741; Myxothiazol. DR DrugBank; DB08690; Ubiquinone Q2. DR MEROPS; M16.973; -. DR MEROPS; M16.981; -. DR GlyGen; P31930; 2 sites, 3 N-linked glycans (1 site), 1 O-linked glycan (1 site). DR iPTMnet; P31930; -. DR MetOSite; P31930; -. DR PhosphoSitePlus; P31930; -. DR SwissPalm; P31930; -. DR BioMuta; UQCRC1; -. DR DMDM; 92090651; -. DR OGP; P31930; -. DR REPRODUCTION-2DPAGE; IPI00013847; -. DR jPOST; P31930; -. DR MassIVE; P31930; -. DR PaxDb; 9606-ENSP00000203407; -. DR PeptideAtlas; P31930; -. DR ProteomicsDB; 54803; -. DR Pumba; P31930; -. DR Antibodypedia; 1257; 374 antibodies from 29 providers. DR DNASU; 7384; -. DR Ensembl; ENST00000203407.6; ENSP00000203407.5; ENSG00000010256.13. DR GeneID; 7384; -. DR KEGG; hsa:7384; -. DR MANE-Select; ENST00000203407.6; ENSP00000203407.5; NM_003365.3; NP_003356.2. DR UCSC; uc003cub.2; human. DR AGR; HGNC:12585; -. DR ClinPGx; PA37216; -. DR CTD; 7384; -. DR DisGeNET; 7384; -. DR GeneCards; UQCRC1; -. DR HGNC; HGNC:12585; UQCRC1. DR HPA; ENSG00000010256; Tissue enhanced (skeletal muscle, tongue). DR MalaCards; UQCRC1; -. DR MIM; 191328; gene. DR MIM; 619279; phenotype. DR OpenTargets; ENSG00000010256; -. DR VEuPathDB; HostDB:ENSG00000010256; -. DR eggNOG; KOG0960; Eukaryota. DR GeneTree; ENSGT00940000158931; -. DR HOGENOM; CLU_009902_4_0_1; -. DR InParanoid; P31930; -. DR OMA; HFAQGEW; -. DR OrthoDB; 10251424at2759; -. DR PAN-GO; P31930; 1 GO annotation based on evolutionary models. DR PhylomeDB; P31930; -. DR BioCyc; MetaCyc:HS00277-MONOMER; -. DR PathwayCommons; P31930; -. DR Reactome; R-HSA-611105; Respiratory electron transport. DR Reactome; R-HSA-9865881; Complex III assembly. DR SignaLink; P31930; -. DR SIGNOR; P31930; -. DR Agora; ENSG00000010256; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 7384; 417 hits in 1176 CRISPR screens. DR CD-CODE; 91857CE7; Nucleolus. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; UQCRC1; human. DR GeneWiki; UQCRC1; -. DR GenomeRNAi; 7384; -. DR Pharos; P31930; Tbio. DR PRO; PR:P31930; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; P31930; protein. DR Bgee; ENSG00000010256; Expressed in apex of heart and 210 other cell types or tissues. DR ExpressionAtlas; P31930; baseline and differential. DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:ComplexPortal. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0098803; C:respiratory chain complex; TAS:ProtInc. DR GO; GO:0045275; C:respiratory chain complex III; IPI:ComplexPortal. DR GO; GO:0046872; F:metal ion binding; IEA:InterPro. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0008121; F:quinol-cytochrome-c reductase activity; TAS:ProtInc. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0009060; P:aerobic respiration; TAS:ProtInc. DR GO; GO:0045333; P:cellular respiration; NAS:ComplexPortal. DR GO; GO:0006122; P:mitochondrial electron transport, ubiquinol to cytochrome c; NAS:ComplexPortal. DR GO; GO:0006119; P:oxidative phosphorylation; TAS:ProtInc. DR GO; GO:0014823; P:response to activity; IEA:Ensembl. DR GO; GO:0043279; P:response to alkaloid; IEA:Ensembl. DR FunFam; 3.30.830.10:FF:000016; Cytochrome b-c1 complex subunit 1, mitochondrial; 1. DR FunFam; 3.30.830.10:FF:000001; Mitochondrial-processing peptidase subunit beta, mitochondrial; 1. DR Gene3D; 3.30.830.10; Metalloenzyme, LuxS/M16 peptidase-like; 2. DR InterPro; IPR011249; Metalloenz_LuxS/M16. DR InterPro; IPR050361; MPP/UQCRC_Complex. DR InterPro; IPR011765; Pept_M16_N. DR InterPro; IPR007863; Peptidase_M16_C. DR PANTHER; PTHR11851:SF116; CYTOCHROME B-C1 COMPLEX SUBUNIT 1, MITOCHONDRIAL; 1. DR PANTHER; PTHR11851; METALLOPROTEASE; 1. DR Pfam; PF00675; Peptidase_M16; 1. DR Pfam; PF05193; Peptidase_M16_C; 1. DR SUPFAM; SSF63411; LuxS/MPP-like metallohydrolase; 2. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Direct protein sequencing; Disease variant; KW Electron transport; Membrane; Mitochondrion; Mitochondrion inner membrane; KW Neuropathy; Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Respiratory chain; Transit peptide; Transport. FT TRANSIT 1..34 FT /note="Mitochondrion" FT /evidence="ECO:0000269|PubMed:8313870, FT ECO:0007744|PubMed:25944712" FT CHAIN 35..480 FT /note="Cytochrome b-c1 complex subunit 1, mitochondrial" FT /id="PRO_0000026786" FT MOD_RES 111 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 138 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q9CZ13" FT MOD_RES 163 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:Q9CZ13" FT MOD_RES 163 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:Q9CZ13" FT MOD_RES 212 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q68FY0" FT MOD_RES 248 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q9CZ13" FT VARIANT 215 FT /note="D -> H (in dbSNP:rs17080284)" FT /id="VAR_034581" FT VARIANT 301 FT /note="N -> S (in dbSNP:rs144710790)" FT /evidence="ECO:0000269|PubMed:10453733, FT ECO:0000269|PubMed:8407948" FT /id="VAR_013629" FT VARIANT 311 FT /note="I -> L (in PKNPY; dbSNP:rs2107843274)" FT /evidence="ECO:0000269|PubMed:33141179" FT /id="VAR_085428" FT VARIANT 314 FT /note="Y -> S (in PKNPY; dbSNP:rs780978963)" FT /evidence="ECO:0000269|PubMed:33141179" FT /id="VAR_085429" FT HELIX 38..44 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 67..69 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 84..86 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 89..95 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 96..99 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 102..104 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 106..116 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 121..124 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 129..132 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 137..139 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 140..150 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 158..175 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 181..192 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 196..198 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 205..208 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 213..222 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 239..250 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 258..260 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 285..294 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 300..311 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 327..332 FT /evidence="ECO:0007829|PDB:5XTE" FT TURN 333..336 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 339..347 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 349..360 FT /evidence="ECO:0007829|PDB:5XTE" FT TURN 362..364 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 365..380 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 385..401 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 406..419 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 426..434 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 438..448 FT /evidence="ECO:0007829|PDB:5XTE" FT TURN 449..451 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 455..461 FT /evidence="ECO:0007829|PDB:5XTE" FT STRAND 463..465 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 468..472 FT /evidence="ECO:0007829|PDB:5XTE" FT HELIX 473..475 FT /evidence="ECO:0007829|PDB:5XTE" SQ SEQUENCE 480 AA; 52646 MW; E76B082166CAF48F CRC64; MAASVVCRAA TAGAQVLLRA RRSPALLRTP ALRSTATFAQ ALQFVPETQV SLLDNGLRVA SEQSSQPTCT VGVWIDVGSR FETEKNNGAG YFLEHLAFKG TKNRPGSALE KEVESMGAHL NAYSTREHTA YYIKALSKDL PKAVELLGDI VQNCSLEDSQ IEKERDVILR EMQENDASMR DVVFNYLHAT AFQGTPLAQA VEGPSENVRK LSRADLTEYL STHYKAPRMV LAAAGGVEHQ QLLDLAQKHL GGIPWTYAED AVPTLTPCRF TGSEIRHRDD ALPFAHVAIA VEGPGWASPD NVALQVANAI IGHYDCTYGG GVHLSSPLAS GAVANKLCQS FQTFSICYAE TGLLGAHFVC DRMKIDDMMF VLQGQWMRLC TSATESEVAR GKNILRNALV SHLDGTTPVC EDIGRSLLTY GRRIPLAEWE SRIAEVDASV VREICSKYIY DQCPAVAGYG PIEQLPDYNR IRSGMFWLRF // ID ZNT10_HUMAN Reviewed; 485 AA. AC Q6XR72; Q49AL9; Q9NPW0; DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot. DT 02-NOV-2010, sequence version 2. DT 28-JAN-2026, entry version 156. DE RecName: Full=Calcium/manganese antiporter SLC30A10 {ECO:0000305|PubMed:30755481}; DE AltName: Full=Solute carrier family 30 member 10 {ECO:0000312|HGNC:HGNC:25355}; DE AltName: Full=Zinc transporter 10; DE Short=ZnT-10; GN Name=SLC30A10 {ECO:0000312|HGNC:HGNC:25355}; GN Synonyms=ZNT10 {ECO:0000303|PubMed:22706290}, ZNT8 {ECO:0000303|Ref.1}; 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] (ISOFORM 1). RA Huang L., Zhou B., Gitschier J.; RT "Characterization of a novel mammalian zinc transporter, ZNT8."; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 90-485 (ISOFORM 3). 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 [5] RP TISSUE SPECIFICITY. RX PubMed=15154973; DOI=10.1186/1471-2164-5-32; RA Seve M., Chimienti F., Devergnas S., Favier A.; RT "In silico identification and expression of SLC30 family genes: an RT expressed sequence tag data mining strategy for the characterization of RT zinc transporters' tissue expression."; RL BMC Genomics 5:32-32(2004). RN [6] RP FUNCTION, INVOLVEMENT IN HMNDYT1, VARIANTS HMNDYT1 PRO-89; 105-ALA--PRO-107 RP DEL; VAL-256 DEL AND PRO-349, AND CHARACTERIZATION OF VARIANTS HMNDYT1 RP PRO-89. RX PubMed=22341972; DOI=10.1016/j.ajhg.2012.01.018; RA Tuschl K., Clayton P.T., Gospe S.M. Jr., Gulab S., Ibrahim S., Singhi P., RA Aulakh R., Ribeiro R.T., Barsottini O.G., Zaki M.S., Del Rosario M.L., RA Dyack S., Price V., Rideout A., Gordon K., Wevers R.A., Chong W.K., RA Mills P.B.; RT "Syndrome of hepatic cirrhosis, dystonia, polycythemia, and RT hypermanganesemia caused by mutations in SLC30A10, a manganese transporter RT in man."; RL Am. J. Hum. Genet. 90:457-466(2012). RN [7] RP INVOLVEMENT IN HMNDYT1, VARIANT SER-167, INDUCTION BY MANGANESE, AND TISSUE RP SPECIFICITY. RX PubMed=22341971; DOI=10.1016/j.ajhg.2012.01.017; RA Quadri M., Federico A., Zhao T., Breedveld G.J., Battisti C., Delnooz C., RA Severijnen L.A., Di Toro Mammarella L., Mignarri A., Monti L., Sanna A., RA Lu P., Punzo F., Cossu G., Willemsen R., Rasi F., Oostra B.A., RA van de Warrenburg B.P., Bonifati V.; RT "Mutations in SLC30A10 cause parkinsonism and dystonia with RT hypermanganesemia, polycythemia, and chronic liver disease."; RL Am. J. Hum. Genet. 90:467-477(2012). RN [8] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=22706290; DOI=10.1039/c2mt20088k; RA Bosomworth H.J., Thornton J.K., Coneyworth L.J., Ford D., Valentine R.A.; RT "Efflux function, tissue-specific expression and intracellular trafficking RT of the Zn transporter ZnT10 indicate roles in adult Zn homeostasis."; RL Metallomics 4:771-779(2012). RN [9] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, INTERACTION WITH RP SLC30A3, AND INDUCTION. RX PubMed=22427991; DOI=10.1371/journal.pone.0033211; RA Patrushev N., Seidel-Rogol B., Salazar G.; RT "Angiotensin II requires zinc and downregulation of the zinc transporters RT ZnT3 and ZnT10 to induce senescence of vascular smooth muscle cells."; RL PLoS ONE 7:E33211-E33211(2012). RN [10] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, MUTAGENESIS OF RP THR-196, AND CHARACTERIZATION OF VARIANTS HMNDYT1 PRO-89 AND RP 105-ALA--PRO-107 DEL. RX PubMed=25319704; DOI=10.1523/jneurosci.2329-14.2014; RA Leyva-Illades D., Chen P., Zogzas C.E., Hutchens S., Mercado J.M., RA Swaim C.D., Morrisett R.A., Bowman A.B., Aschner M., Mukhopadhyay S.; RT "SLC30A10 is a cell surface-localized manganese efflux transporter, and RT parkinsonism-causing mutations block its intracellular trafficking and RT efflux activity."; RL J. Neurosci. 34:14079-14095(2014). RN [11] RP INDUCTION. RX PubMed=25582195; DOI=10.1128/mcb.01298-14; RA Ogo O.A., Tyson J., Cockell S.J., Howard A., Valentine R.A., Ford D.; RT "The zinc finger protein ZNF658 regulates the transcription of genes RT involved in zinc homeostasis and affects ribosome biogenesis through the RT zinc transcriptional regulatory element."; RL Mol. Cell. Biol. 35:977-987(2015). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP ASN-43; CYS-52 AND LEU-242. RX PubMed=27226609; DOI=10.1074/jbc.m116.728014; RA Nishito Y., Tsuji N., Fujishiro H., Takeda T.A., Yamazaki T., Teranishi F., RA Okazaki F., Matsunaga A., Tuschl K., Rao R., Kono S., Miyajima H., RA Narita H., Himeno S., Kambe T.; RT "Direct comparison of manganese detoxification/efflux proteins and RT molecular characterization of ZnT10 protein as a manganese transporter."; RL J. Biol. Chem. 291:14773-14787(2016). RN [13] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP GLU-25; ASP-40; ASN-43; ASP-47; ASN-127; HIS-244; ASP-248; HIS-333 AND RP HIS-350. RX PubMed=27307044; DOI=10.1074/jbc.m116.726935; RA Zogzas C.E., Aschner M., Mukhopadhyay S.; RT "Structural elements in the transmembrane and cytoplasmic domains of the RT metal transporter SLC30A10 are required for its manganese efflux RT activity."; RL J. Biol. Chem. 291:15940-15957(2016). RN [14] RP FUNCTION, TRANSPORTER ACTIVITY, SUBUNIT, INTERACTION WITH SLC30A2; SLC30A3 RP AND SLC30A4, SUBCELLULAR LOCATION, AND MUTAGENESIS OF TYR-4. RX PubMed=26728129; DOI=10.1111/tra.12371; RA Zhao Y., Feresin R.G., Falcon-Perez J.M., Salazar G.; RT "Differential targeting of SLC30A10/ZnT10 heterodimers to endolysosomal RT compartments modulates EGF-induced MEK/ERK1/2 activity."; RL Traffic 17:267-288(2016). RN [15] RP FUNCTION, TRANSPORTER ACTIVITY, MUTAGENESIS OF ASN-43; ASP-47; HIS-244 AND RP ASP-248, AND SITE. RX PubMed=30755481; DOI=10.1074/jbc.ra118.006816; RA Levy M., Elkoshi N., Barber-Zucker S., Hoch E., Zarivach R., RA Hershfinkel M., Sekler I.; RT "Zinc transporter 10 (ZnT10)-dependent extrusion of cellular Mn2+ is driven RT by an active Ca2+-coupled exchange."; RL J. Biol. Chem. 294:5879-5889(2019). CC -!- FUNCTION: Calcium:manganese antiporter of the plasma membrane mediating CC the efflux of intracellular manganese coupled to an active CC extracellular calcium exchange (PubMed:30755481). Required for CC intracellular manganese homeostasis, an essential cation for the CC function of several enzymes, including some crucially important for the CC metabolism of neurotransmitters and other neuronal metabolic pathways. CC Manganese can also be cytotoxic and induce oxidative stress, CC mitochondrial dysfunction and apoptosis (PubMed:22341972, CC PubMed:25319704, PubMed:26728129, PubMed:27226609, PubMed:27307044). CC Could also have an intracellular zinc ion transporter activity, CC directly regulating intracellular zinc ion homeostasis and more CC indirectly various signaling pathway and biological processes CC (PubMed:22427991, PubMed:26728129). {ECO:0000269|PubMed:22341972, CC ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:25319704, CC ECO:0000269|PubMed:26728129, ECO:0000269|PubMed:27226609, CC ECO:0000269|PubMed:27307044, ECO:0000269|PubMed:30755481}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Mn(2+)(out) + Ca(2+)(in) = Mn(2+)(in) + Ca(2+)(out); CC Xref=Rhea:RHEA:73059, ChEBI:CHEBI:29035, ChEBI:CHEBI:29108; CC Evidence={ECO:0000269|PubMed:25319704, ECO:0000269|PubMed:27226609, CC ECO:0000269|PubMed:27307044, ECO:0000269|PubMed:30755481}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Zn(2+)(in) = Zn(2+)(out); Xref=Rhea:RHEA:29351, CC ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:26728129}; CC -!- SUBUNIT: Forms homodimers. Forms heterodimers and high-molecular weight CC oligomers with SLC30A3, SLC30A2 and SLC30A4; heterodimerization is CC mediated by covalent-bound tyrosine residues, occurs probably in a CC tissue-specific manner and could mediate the intracellular zinc CC transport activity into early endosomes and recycling endosomes. CC {ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:26728129}. CC -!- INTERACTION: CC Q6XR72; Q9BRI3: SLC30A2; NbExp=4; IntAct=EBI-13917996, EBI-8644112; CC Q6XR72; Q99726: SLC30A3; NbExp=3; IntAct=EBI-13917996, EBI-10294651; CC Q6XR72; O14863: SLC30A4; NbExp=2; IntAct=EBI-13917996, EBI-13918058; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:22706290, CC ECO:0000269|PubMed:25319704, ECO:0000269|PubMed:26728129, CC ECO:0000269|PubMed:27226609, ECO:0000269|PubMed:27307044}; Multi-pass CC membrane protein {ECO:0000255}. Golgi apparatus membrane CC {ECO:0000269|PubMed:22706290, ECO:0000269|PubMed:27226609}; Multi-pass CC membrane protein {ECO:0000255}. Recycling endosome membrane CC {ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:26728129}. Early CC endosome membrane {ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:26728129}; Multi-pass membrane protein CC {ECO:0000255}. Note=Localization to the Golgi and plasma membrane is CC regulated by zinc. {ECO:0000269|PubMed:22706290}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q6XR72-4; Sequence=Displayed; CC Name=2; CC IsoId=Q6XR72-2; Sequence=VSP_029863; CC Name=3; CC IsoId=Q6XR72-3; Sequence=VSP_029864, VSP_029865; CC -!- TISSUE SPECIFICITY: Specifically expressed in fetal liver and fetal CC brain (PubMed:15154973). Expressed in adult tissues with relative CC levels small intestine > liver > testes > brain > ovary > colon > CC cervix > prostate > placenta (PubMed:22706290). Expressed in liver and CC neurons of the nervous system (at protein level) (PubMed:22341971). CC {ECO:0000269|PubMed:15154973, ECO:0000269|PubMed:22341971, CC ECO:0000269|PubMed:22706290}. CC -!- INDUCTION: Down-regulated by zinc (PubMed:22427991, PubMed:22706290, CC PubMed:25582195). Down-regulated by angiotensin-2 (PubMed:22427991). CC Up-regulated by manganese (PubMed:22341971). CC {ECO:0000269|PubMed:22341971, ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:22706290, ECO:0000269|PubMed:25582195}. CC -!- DISEASE: Hypermanganesemia with dystonia 1 (HMNDYT1) [MIM:613280]: A CC metabolic autosomal recessive disorder characterized by dystonia, CC parkinsonism, extrapyramidal signs, severe hypermanganesemia, CC polycythemia, and chronic hepatic disease, including steatosis and CC cirrhosis. {ECO:0000269|PubMed:22341971, ECO:0000269|PubMed:22341972, CC ECO:0000269|PubMed:25319704}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 2]: 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 cation diffusion facilitator (CDF) CC transporter (TC 2.A.4) family. SLC30A subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAP44332.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in position 427.; 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; AY212919; AAP44332.1; ALT_SEQ; mRNA. DR EMBL; AL359609; CAB94880.1; -; mRNA. DR EMBL; AC093562; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC036078; AAH36078.1; -; mRNA. DR CCDS; CCDS31026.1; -. [Q6XR72-4] DR PIR; T50628; T50628. DR RefSeq; NP_061183.2; NM_018713.2. [Q6XR72-4] DR AlphaFoldDB; Q6XR72; -. DR SMR; Q6XR72; -. DR BioGRID; 120703; 181. DR ComplexPortal; CPX-8462; ZNT10 calcium-coupled manganese antiporter homodimer. DR ComplexPortal; CPX-8463; ZNT2-ZNT10 proton-coupled zinc antiporter complex. DR ComplexPortal; CPX-8464; ZNT3-ZNT10 proton-coupled zinc antiporter complex. DR ComplexPortal; CPX-8465; ZNT4-ZNT10 proton-coupled zinc antiporter complex. DR FunCoup; Q6XR72; 245. DR IntAct; Q6XR72; 179. DR STRING; 9606.ENSP00000355893; -. DR DrugBank; DB06757; Manganese cation. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR TCDB; 2.A.4.2.5; the cation diffusion facilitator (cdf) family. DR GlyGen; Q6XR72; 1 site. DR iPTMnet; Q6XR72; -. DR PhosphoSitePlus; Q6XR72; -. DR BioMuta; SLC30A10; -. DR DMDM; 311033506; -. DR jPOST; Q6XR72; -. DR MassIVE; Q6XR72; -. DR PaxDb; 9606-ENSP00000355893; -. DR PeptideAtlas; Q6XR72; -. DR ProteomicsDB; 67813; -. [Q6XR72-4] DR ProteomicsDB; 67814; -. [Q6XR72-2] DR ProteomicsDB; 67815; -. [Q6XR72-3] DR Antibodypedia; 3072; 116 antibodies from 18 providers. DR DNASU; 55532; -. DR Ensembl; ENST00000356609.2; ENSP00000349018.2; ENSG00000196660.13. [Q6XR72-3] DR Ensembl; ENST00000366926.4; ENSP00000355893.4; ENSG00000196660.13. [Q6XR72-4] DR GeneID; 55532; -. DR KEGG; hsa:55532; -. DR MANE-Select; ENST00000366926.4; ENSP00000355893.4; NM_018713.3; NP_061183.2. DR UCSC; uc001hlw.4; human. [Q6XR72-4] DR AGR; HGNC:25355; -. DR ClinPGx; PA142670903; -. DR CTD; 55532; -. DR DisGeNET; 55532; -. DR GeneCards; SLC30A10; -. DR GeneReviews; SLC30A10; -. DR HGNC; HGNC:25355; SLC30A10. DR HPA; ENSG00000196660; Group enriched (intestine, liver). DR MalaCards; SLC30A10; -. DR MIM; 611146; gene. DR MIM; 613280; phenotype. DR OpenTargets; ENSG00000196660; -. DR Orphanet; 309854; Cirrhosis-dystonia-polycythemia-hypermanganesemia syndrome. DR VEuPathDB; HostDB:ENSG00000196660; -. DR eggNOG; KOG1483; Eukaryota. DR GeneTree; ENSGT00940000159967; -. DR HOGENOM; CLU_1239780_0_0_1; -. DR InParanoid; Q6XR72; -. DR OMA; FQDCASW; -. DR OrthoDB; 29444at2759; -. DR PAN-GO; Q6XR72; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q6XR72; -. DR PathwayCommons; Q6XR72; -. DR Reactome; R-HSA-425410; Metal ion SLC transporters. DR SignaLink; Q6XR72; -. DR Agora; ENSG00000196660; -. DR BioGRID-ORCS; 55532; 11 hits in 1155 CRISPR screens. DR ChiTaRS; SLC30A10; human. DR GenomeRNAi; 55532; -. DR Pharos; Q6XR72; Tbio. DR PRO; PR:Q6XR72; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q6XR72; protein. DR Bgee; ENSG00000196660; Expressed in jejunal mucosa and 75 other cell types or tissues. DR GO; GO:0005769; C:early endosome; IDA:UniProtKB. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB. DR GO; GO:0055038; C:recycling endosome membrane; IDA:UniProtKB. DR GO; GO:0140983; F:calcium:manganese antiporter activity; IDA:UniProtKB. DR GO; GO:0005384; F:manganese ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:1904385; P:cellular response to angiotensin; IDA:UniProtKB. DR GO; GO:0010312; P:detoxification of zinc ion; IBA:GO_Central. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0030026; P:intracellular manganese ion homeostasis; IDA:UniProtKB. DR GO; GO:0006882; P:intracellular zinc ion homeostasis; IDA:UniProtKB. DR GO; GO:0140048; P:manganese ion export across plasma membrane; IDA:UniProtKB. DR GO; GO:0006828; P:manganese ion transport; IMP:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0062111; P:zinc ion import into organelle; IDA:UniProtKB. DR GO; GO:0071577; P:zinc ion transmembrane transport; IBA:GO_Central. DR Gene3D; 1.20.1510.10; Cation efflux protein transmembrane domain; 1. DR InterPro; IPR002524; Cation_efflux. DR InterPro; IPR027470; Cation_efflux_CTD. DR InterPro; IPR058533; Cation_efflux_TM. DR InterPro; IPR027469; Cation_efflux_TMD_sf. DR NCBIfam; TIGR01297; CDF; 1. DR PANTHER; PTHR45820:SF3; CALCIUM_MANGANESE ANTIPORTER SLC30A10; 1. DR PANTHER; PTHR45820; FI23527P1; 1. DR Pfam; PF01545; Cation_efflux; 1. DR Pfam; PF16916; ZT_dimer; 1. DR SUPFAM; SSF161111; Cation efflux protein transmembrane domain-like; 1. PE 1: Evidence at protein level; KW Alternative splicing; Antiport; Cell membrane; Disease variant; Dystonia; KW Endosome; Golgi apparatus; Ion transport; Manganese; Membrane; KW Neurodegeneration; Parkinsonism; Proteomics identification; KW Reference proteome; Transmembrane; Transmembrane helix; Transport; Zinc; KW Zinc transport. FT CHAIN 1..485 FT /note="Calcium/manganese antiporter SLC30A10" FT /id="PRO_0000312580" FT TOPO_DOM 1..10 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 11..31 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 32..40 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 41..61 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 62..81 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 82..102 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 103..113 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 114..134 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 135..244 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 245..265 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 266..278 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 279..299 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 300..485 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 167..196 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 308..485 FT /note="Required for plasma membrane localization" FT /evidence="ECO:0000269|PubMed:25319704" FT SITE 43 FT /note="Important for coupling of manganese to calcium FT transport" FT /evidence="ECO:0000269|PubMed:30755481" FT VAR_SEQ 1..245 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_029863" FT VAR_SEQ 214..223 FT /note="GDSFNTQNEP -> ELIHNTRFLL (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_029864" FT VAR_SEQ 224..485 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_029865" FT VARIANT 89 FT /note="L -> P (in HMNDYT1; loss of localization to the FT plasma membrane; retained in the endoplasmic reticulum; FT increased proteasomal degradation; loss of function in FT intracellular manganese ion homeostasis; FT dbSNP:rs281860284)" FT /evidence="ECO:0000269|PubMed:22341972, FT ECO:0000269|PubMed:25319704" FT /id="VAR_072573" FT VARIANT 105..107 FT /note="Missing (in HMNDYT1; loss of localization to the FT plasma membrane; retained in the endoplasmic reticulum; FT increased proteasomal degradation; decreased function in FT intracellular manganese ion homeostasis)" FT /evidence="ECO:0000269|PubMed:22341972, FT ECO:0000269|PubMed:25319704" FT /id="VAR_072574" FT VARIANT 167 FT /note="F -> S (in dbSNP:rs281860286)" FT /evidence="ECO:0000269|PubMed:22341971" FT /id="VAR_072575" FT VARIANT 256 FT /note="Missing (in HMNDYT1)" FT /evidence="ECO:0000269|PubMed:22341972" FT /id="VAR_072576" FT VARIANT 349 FT /note="L -> P (in HMNDYT1; dbSNP:rs281860291)" FT /evidence="ECO:0000269|PubMed:22341972" FT /id="VAR_072577" FT MUTAGEN 4 FT /note="Y->F: Decreased interaction with SLC30A3. No effect FT on self-association. Decreased zinc ion transmembrane FT transporter activity. Decreased EGF-induced ERK1/2 FT phosphorylation." FT /evidence="ECO:0000269|PubMed:26728129" FT MUTAGEN 25 FT /note="E->A: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 40 FT /note="D->A: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 43 FT /note="N->A: No effect on localization to the plasma FT membrane. Changed calcium:manganese antiporter activity. FT Enhanced coupling between manganese and calcium exchange." FT /evidence="ECO:0000269|PubMed:27307044, FT ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->D: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->H: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity. FT Loss of calcium:manganese antiporter activity and increased FT zinc ion transmembrane transporter activity; when FT associated with V-52 and F-242." FT /evidence="ECO:0000269|PubMed:27226609, FT ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->T: Loss of calcium:manganese antiporter activity. FT Uncoupling between manganese and calcium exchange." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 47 FT /note="D->A: No effect on localization to the plasma FT membrane. No effect on calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 47 FT /note="D->E: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 52 FT /note="C->V: Loss of calcium:manganese antiporter activity FT and increased zinc ion transmembrane transporter activity; FT when associated with H-43 and F-242." FT /evidence="ECO:0000269|PubMed:27226609" FT MUTAGEN 127 FT /note="N->A: No effect on localization to the plasma FT membrane. No effect on localization to the plasma membrane FT and decreased calcium:manganese antiporter activity; when FT associated with A-244." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 196 FT /note="T->P: Loss of localization to the plasma membrane." FT /evidence="ECO:0000269|PubMed:25319704" FT MUTAGEN 242 FT /note="L->F: Loss of calcium:manganese antiporter activity FT and increased zinc ion transmembrane transporter activity; FT when associated with H-43 and V-52." FT /evidence="ECO:0000269|PubMed:27226609" FT MUTAGEN 244 FT /note="H->A: No effect on localization to the plasma FT membrane. No effect on localization to the plasma membrane FT and decreased calcium:manganese antiporter activity; when FT associated with A-127." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 244 FT /note="H->D: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 248 FT /note="D->A: No effect on localization to the plasma FT membrane. Loss of manganese ion export across plasma FT membrane." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 333 FT /note="H->A: Decreased calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 350 FT /note="H->A: Decreased calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" SQ SEQUENCE 485 AA; 52684 MW; 96A3495EF026DE94 CRC64; MGRYSGKTCR LLFMLVLTVA FFVAELVSGY LGNSIALLSD SFNMLSDLIS LCVGLSAGYI ARRPTRGFSA TYGYARAEVV GALSNAVFLT ALCFTIFVEA VLRLARPERI DDPELVLIVG VLGLLVNVVG LLIFQDCAAW FACCLRGRSR RLQQRQQLAE GCVPGAFGGP QGAEDPRRAA DPTAPGSDSA VTLRGTSVER KREKGATVFA NVAGDSFNTQ NEPEDMMKKE KKSEALNIRG VLLHVMGDAL GSVVVVITAI IFYVLPLKSE DPCNWQCYID PSLTVLMVII ILSSAFPLIK ETAAILLQMV PKGVNMEELM SKLSAVPGIS SVHEVHIWEL VSGKIIATLH IKYPKDRGYQ DASTKIREIF HHAGIHNVTI QFENVDLKEP LEQKDLLLLC NSPCISKGCA KQLCCPPGAL PLAHVNGCAE HNGGPSLDTY GSDGLSRRDA REVAIEVSLD SCLSDHGQSL NKTQEDQCYV NRTHF //