ID DOCK3_HUMAN Reviewed; 2030 AA. AC Q8IZD9; O15017; DT 03-JUL-2003, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2003, sequence version 1. DT 28-JAN-2026, entry version 170. DE RecName: Full=Dedicator of cytokinesis protein 3 {ECO:0000303|PubMed:14569117}; DE AltName: Full=Modifier of cell adhesion {ECO:0000250|UniProtKB:Q8CIQ7}; DE AltName: Full=PS binding protein {ECO:0000303|PubMed:10854253}; DE Short=PBP {ECO:0000303|PubMed:10854253}; DE AltName: Full=Presenilin-binding protein {ECO:0000305|PubMed:10854253}; GN Name=DOCK3 {ECO:0000303|PubMed:14569117, ECO:0000312|HGNC:HGNC:2989}; GN Synonyms=KIAA0299, MOCA {ECO:0000250|UniProtKB:Q8CIQ7}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=10854253; DOI=10.1046/j.1471-4159.2000.0750109.x; RA Kashiwa A., Yoshida H., Lee S., Paladino T., Liu Y., Chen Q., Dargusch R., RA Schubert D., Kimura H.; RT "Isolation and characterization of novel presenilin binding protein."; RL J. Neurochem. 75:109-116(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND CHROMOSOMAL REARRANGEMENT. RX PubMed=14569117; DOI=10.1136/jmg.40.10.733; RA De Silva M.G., Elliott K., Dahl H.-H.M., Fitzpatrick E., Wilcox S., RA Delatycki M., Williamson R., Efron D., Lynch M., Forrest S.; RT "Disruption of a novel member of a sodium/hydrogen exchanger family and RT DOCK3 is associated with an attention deficit hyperactivity disorder-like RT phenotype."; RL J. Med. Genet. 40:733-740(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 124-2030. RC TISSUE=Brain; RX PubMed=9205841; DOI=10.1093/dnares/4.2.141; RA Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N., RA Tanaka A., Kotani H., Nomura N., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. VII. The RT complete sequences of 100 new cDNA clones from brain which can code for RT large proteins in vitro."; RL DNA Res. 4:141-150(1997). RN [4] RP TISSUE SPECIFICITY. RX PubMed=11696419; DOI=10.1016/s0002-9440(10)63005-2; RA Chen Q., Yoshida H., Schubert D., Maher P., Mallory M., Masliah E.; RT "Presenilin binding protein is associated with neurofibrillary alterations RT in Alzheimer's disease and stimulates tau phosphorylation."; RL Am. J. Pathol. 159:1597-1602(2001). RN [5] RP NOMENCLATURE. RX PubMed=12432077; DOI=10.1242/jcs.00219; RA Cote J.-F., Vuori K.; RT "Identification of an evolutionarily conserved superfamily of DOCK180- RT related proteins with guanine nucleotide exchange activity."; RL J. Cell Sci. 115:4901-4913(2002). RN [6] RP INVOLVEMENT IN NEDIDHA, AND VARIANT NEDIDHA 128-GLN--GLN-2030 DEL. RX PubMed=28195318; DOI=10.1111/cge.12995; RA Helbig K.L., Mroske C., Moorthy D., Sajan S.A., Velinov M.; RT "Biallelic loss-of-function variants in DOCK3 cause muscle hypotonia, RT ataxia, and intellectual disability."; RL Clin. Genet. 92:430-433(2017). RN [7] RP INVOLVEMENT IN NEDIDHA. RX PubMed=29130632; DOI=10.1002/ajmg.a.38517; RA Iwata-Otsubo A., Ritter A.L., Weckselbatt B., Ryan N.R., Burgess D., RA Conlin L.K., Izumi K.; RT "DOCK3-related neurodevelopmental syndrome: Biallelic intragenic deletion RT of DOCK3 in a boy with developmental delay and hypotonia."; RL Am. J. Med. Genet. A 176:241-245(2018). RN [8] RP INVOLVEMENT IN NEDIDHA, AND VARIANTS NEDIDHA GLN-392; ARG-1296 AND RP LEU-1674. RX PubMed=30976111; DOI=10.1038/s41431-019-0397-2; RA Wiltrout K., Ferrer A., van de Laar I., Namekata K., Harada T., Klee E.W., RA Zimmerman M.T., Cousin M.A., Kempainen J.L., Babovic-Vuksanovic D., RA van Slegtenhorst M.A., Aarts-Tesselaar C.D., Schnur R.E., Andrews M., RA Shinawi M.; RT "Variants in DOCK3 cause developmental delay and hypotonia."; RL Eur. J. Hum. Genet. 27:1225-1234(2019). CC -!- FUNCTION: Potential guanine nucleotide exchange factor (GEF). GEF CC proteins activate some small GTPases by exchanging bound GDP for free CC GTP. Its interaction with presenilin proteins as well as its ability to CC stimulate Tau/MAPT phosphorylation suggest that it may be involved in CC Alzheimer disease. Ectopic expression in nerve cells decreases the CC secretion of amyloid-beta APBA1 protein and lowers the rate of cell- CC substratum adhesion, suggesting that it may affect the function of some CC small GTPase involved in the regulation of actin cytoskeleton or cell CC adhesion receptors (By similarity). {ECO:0000250}. CC -!- SUBUNIT: Interacts with PSEN1; this interaction mediates the membrane CC association of DOCK3 (By similarity). Interacts with PSEN2 (By CC similarity). Interacts with CRK (By similarity). CC {ECO:0000250|UniProtKB:Q8CIQ7}. CC -!- INTERACTION: CC Q8IZD9; Q13017-1: ARHGAP5; NbExp=2; IntAct=EBI-1752361, EBI-25409992; CC Q8IZD9; P49639: HOXA1; NbExp=3; IntAct=EBI-1752361, EBI-740785; CC Q8IZD9; P16333: NCK1; NbExp=3; IntAct=EBI-1752361, EBI-389883; CC Q8IZD9; Q14511: NEDD9; NbExp=2; IntAct=EBI-1752361, EBI-2108053; CC Q8IZD9; Q9H8W4: PLEKHF2; NbExp=3; IntAct=EBI-1752361, EBI-742388; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q8CIQ7}. CC Note=Becomes membrane associated when interacts with PSEN1. CC {ECO:0000250|UniProtKB:Q8CIQ7}. CC -!- TISSUE SPECIFICITY: In normal brains, it is localized in the neuropil, CC and occasionally in the pyramidal cells, while in Alzheimer disease CC brains, it is associated with neurofibrillary tangles. CC {ECO:0000269|PubMed:11696419}. CC -!- DOMAIN: The DOCKER domain may mediate some GEF activity. {ECO:0000250}. CC -!- DISEASE: Note=A chromosomal aberration involving DOCK3 has been found CC in a family with early-onset behavioral/developmental disorder with CC features of attention deficit-hyperactivity disorder and intellectual CC disability. Inversion inv(3)(p14:q21). The inversion disrupts DOCK3 and CC SLC9A9. {ECO:0000269|PubMed:14569117}. CC -!- DISEASE: Neurodevelopmental disorder with impaired intellectual CC development, hypotonia, and ataxia (NEDIDHA) [MIM:618292]: An autosomal CC recessive disease characterized by global developmental delay, CC hypotonia, ataxic gait, hyporeflexia, poor or absent speech, and CC variable and mild dysmorphic features. {ECO:0000269|PubMed:28195318, CC ECO:0000269|PubMed:29130632, ECO:0000269|PubMed:30976111}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the DOCK family. {ECO:0000255|PROSITE- CC ProRule:PRU00983}. 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; AY145303; AAN12301.1; -; mRNA. DR EMBL; AY254099; AAP80572.1; -; mRNA. DR EMBL; AB002297; BAA20759.1; -; mRNA. DR CCDS; CCDS46835.1; -. DR RefSeq; NP_004938.1; NM_004947.5. DR AlphaFoldDB; Q8IZD9; -. DR SMR; Q8IZD9; -. DR BioGRID; 108130; 65. DR FunCoup; Q8IZD9; 863. DR IntAct; Q8IZD9; 44. DR STRING; 9606.ENSP00000266037; -. DR GlyGen; Q8IZD9; 2 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (1 site). DR iPTMnet; Q8IZD9; -. DR PhosphoSitePlus; Q8IZD9; -. DR SwissPalm; Q8IZD9; -. DR BioMuta; DOCK3; -. DR DMDM; 32469734; -. DR jPOST; Q8IZD9; -. DR MassIVE; Q8IZD9; -. DR PaxDb; 9606-ENSP00000266037; -. DR PeptideAtlas; Q8IZD9; -. DR ProteomicsDB; 71332; -. DR Antibodypedia; 46085; 83 antibodies from 18 providers. DR DNASU; 1795; -. DR Ensembl; ENST00000266037.10; ENSP00000266037.8; ENSG00000088538.14. DR GeneID; 1795; -. DR KEGG; hsa:1795; -. DR MANE-Select; ENST00000266037.10; ENSP00000266037.8; NM_004947.5; NP_004938.1. DR UCSC; uc011bds.2; human. DR AGR; HGNC:2989; -. DR ClinPGx; PA27455; -. DR CTD; 1795; -. DR DisGeNET; 1795; -. DR GeneCards; DOCK3; -. DR HGNC; HGNC:2989; DOCK3. DR HPA; ENSG00000088538; Tissue enhanced (brain, thyroid gland). DR MalaCards; DOCK3; -. DR MIM; 603123; gene. DR MIM; 618292; phenotype. DR OpenTargets; ENSG00000088538; -. DR Orphanet; 528084; Non-specific syndromic intellectual disability. DR VEuPathDB; HostDB:ENSG00000088538; -. DR eggNOG; KOG1998; Eukaryota. DR GeneTree; ENSGT00940000155514; -. DR HOGENOM; CLU_000595_2_0_1; -. DR InParanoid; Q8IZD9; -. DR OMA; XQYETVV; -. DR OrthoDB; 18896at2759; -. DR PAN-GO; Q8IZD9; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q8IZD9; -. DR PathwayCommons; Q8IZD9; -. DR Reactome; R-HSA-9013149; RAC1 GTPase cycle. DR Reactome; R-HSA-9013404; RAC2 GTPase cycle. DR Reactome; R-HSA-9013408; RHOG GTPase cycle. DR Reactome; R-HSA-9032759; NTRK2 activates RAC1. DR Reactome; R-HSA-983231; Factors involved in megakaryocyte development and platelet production. DR SignaLink; Q8IZD9; -. DR SIGNOR; Q8IZD9; -. DR Agora; ENSG00000088538; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 1795; 12 hits in 1149 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; DOCK3; human. DR GeneWiki; Dock3; -. DR GenomeRNAi; 1795; -. DR Pharos; Q8IZD9; Tbio. DR PRO; PR:Q8IZD9; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; Q8IZD9; protein. DR Bgee; ENSG00000088538; Expressed in frontal pole and 130 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0005096; F:GTPase activator activity; IEA:InterPro. DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IBA:GO_Central. DR GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW. DR GO; GO:0031267; F:small GTPase binding; IBA:GO_Central. DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome. DR GO; GO:0051056; P:regulation of small GTPase mediated signal transduction; TAS:Reactome. DR GO; GO:0007264; P:small GTPase-mediated signal transduction; IEA:InterPro. DR CDD; cd08695; C2_Dock-B; 1. DR CDD; cd11704; DHR2_DOCK3; 1. DR CDD; cd12048; SH3_DOCK3_B; 1. DR FunFam; 1.25.40.410:FF:000003; Dedicator of cytokinesis protein 4; 1. DR FunFam; 2.30.30.40:FF:000057; Dedicator of cytokinesis protein 4; 1. DR FunFam; 2.60.40.150:FF:000045; Dedicator of cytokinesis protein 4; 1. DR FunFam; 1.20.1270.350:FF:000001; dedicator of cytokinesis protein 4; 1. DR Gene3D; 1.20.58.740; -; 1. DR Gene3D; 1.25.40.410; -; 1. DR Gene3D; 2.60.40.150; C2 domain; 1. DR Gene3D; 1.20.1270.350; Dedicator of cytokinesis N-terminal subdomain; 1. DR Gene3D; 2.30.30.40; SH3 Domains; 1. DR InterPro; IPR016024; ARM-type_fold. DR InterPro; IPR037811; C2_Dock-B. DR InterPro; IPR027007; C2_DOCK-type_domain. DR InterPro; IPR035892; C2_domain_sf. DR InterPro; IPR026800; DHR2_DOCK3. DR InterPro; IPR026791; DOCK. DR InterPro; IPR035767; DOCK3_SH3. DR InterPro; IPR043161; DOCK_C_lobe_A. DR InterPro; IPR043162; DOCK_C_lobe_C. DR InterPro; IPR032376; DOCK_N. DR InterPro; IPR042455; DOCK_N_sub1. DR InterPro; IPR027357; DOCKER_dom. DR InterPro; IPR046769; DOCKER_Lobe_A. DR InterPro; IPR046770; DOCKER_Lobe_B. DR InterPro; IPR046773; DOCKER_Lobe_C. DR InterPro; IPR036028; SH3-like_dom_sf. DR InterPro; IPR001452; SH3_domain. DR InterPro; IPR056372; TPR_DOCK. DR PANTHER; PTHR45653; DEDICATOR OF CYTOKINESIS; 1. DR PANTHER; PTHR45653:SF4; DEDICATOR OF CYTOKINESIS PROTEIN 3; 1. DR Pfam; PF06920; DHR-2_Lobe_A; 1. DR Pfam; PF20422; DHR-2_Lobe_B; 1. DR Pfam; PF20421; DHR-2_Lobe_C; 1. DR Pfam; PF14429; DOCK-C2; 1. DR Pfam; PF16172; DOCK_N; 1. DR Pfam; PF07653; SH3_2; 1. DR Pfam; PF23554; TPR_DOCK; 1. DR SMART; SM00326; SH3; 1. DR SUPFAM; SSF48371; ARM repeat; 1. DR SUPFAM; SSF50044; SH3-domain; 1. DR PROSITE; PS51650; C2_DOCK; 1. DR PROSITE; PS51651; DOCKER; 1. DR PROSITE; PS50002; SH3; 1. PE 1: Evidence at protein level; KW Chromosomal rearrangement; Cytoplasm; Disease variant; KW Guanine-nucleotide releasing factor; Phosphoprotein; KW Proteomics identification; Reference proteome; SH3 domain; SH3-binding. FT CHAIN 1..2030 FT /note="Dedicator of cytokinesis protein 3" FT /id="PRO_0000189988" FT DOMAIN 6..67 FT /note="SH3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192" FT DOMAIN 421..599 FT /note="C2 DOCK-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00983" FT DOMAIN 1228..1635 FT /note="DOCKER" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00984" FT REGION 1641..1662 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1734..1771 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1849..1927 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1951..2030 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 1970..1976 FT /note="SH3-binding" FT /evidence="ECO:0000255" FT COMPBIAS 1734..1754 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1755..1765 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1880..1902 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1967..1977 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1984..2001 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2014..2030 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 1658 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8CIQ7" FT VARIANT 128..2030 FT /note="Missing (in NEDIDHA)" FT /evidence="ECO:0000269|PubMed:28195318" FT /id="VAR_081831" FT VARIANT 392 FT /note="R -> Q (in NEDIDHA; uncertain significance; FT dbSNP:rs199600118)" FT /evidence="ECO:0000269|PubMed:30976111" FT /id="VAR_081832" FT VARIANT 1296 FT /note="K -> R (in NEDIDHA; uncertain significance; FT dbSNP:rs201184598)" FT /evidence="ECO:0000269|PubMed:30976111" FT /id="VAR_081833" FT VARIANT 1674 FT /note="M -> L (in NEDIDHA; uncertain significance; FT dbSNP:rs142515812)" FT /evidence="ECO:0000269|PubMed:30976111" FT /id="VAR_081834" SQ SEQUENCE 2030 AA; 233103 MW; FF87E874B926C1C7 CRC64; MWTPTEEEKY GVVICSFRGS VPQGLVLEIG ETVQILEKCE GWYRGVSTKK PNVKGIFPAN YIHLKKAIVS NRGQYETVVP LEDSIVTEVT ATLQEWASLW KQLYVKHKVD LFYKLRHVMN ELIDLRRQLL SGHLTQDQVR EVKRHITVRL DWGNEHLGLD LVPRKDFEVV DSDQISVSDL YKMHLSSRQS VQQSTSQVDT MRPRHGETCR MPVPHHFFLS LKSFTYNTIG EDTDVFFSLY DMREGKQISE RFLVRLNKNG GPRNPEKIER MCALFTDLSS KDMKRDLYIV AHVIRIGRML LNDSKKGPPH LHYRRPYGCA VLSILDVLQS LTEVKEEKDF VLKVYTCNNE SEWSQIHENI IRKSSAKYSA PSASHGLIIS LQLLRGDMEQ IRRENPMIFN RGLAITRKLG FPDVIMPGDI RNDLYLTLEK GDFERGGKSV QKNIEVTMYV LYADGEILKD CISLGSGEPN RSSYHSFVLY HSNSPRWGEI IKLPIPIDRF RGSHLRFEFR HCSTKDKGEK KLFGFAFSTL MRDDGTTLSD DIHELYVYKC DENSTFNNHA LYLGLPCCKE DYNGCPNIPS SLIFQRSTKE SFFISTQLSS TKLTQNVDLL ALLKWKAFPD RIMDVLGRLR HVSGEEIVKF LQDILDTLFV ILDDNTEKYG LLVFQSLVFI INLLRDIKYF HFRPVMDTYI QKHFAGALAY KELIRCLKWY MDCSAELIRQ DHIQEAMRAL EYLFKFIVQS RILYSRATCG MEEEQFRSSI QELFQSIRFV LSLDSRNSET LLFTQAALLN SFPTIFDELL QMFTVQEVAE FVRGTLGSMP STVHIGQSMD VVKLQSIART VDSRLFSFSE SRRILLPVVL HHIHLHLRQQ KELLICSGIL GSIFSIVKTS SLEADVMEEV EMMVESLLDV LLQTLLTIMS KSHAQEAVRG QRCPQCTAEI TGEYVSCLLS LLRQMCDTHF QHLLDNFQSK DELKEFLLKI FCVFRNLMKM SVFPRDWMVM RLLTSNIIVT TVQYLSSALH KNFTETDFDF KVWNSYFSLA VLFINQPSLQ LEIITSAKRK KILDKYGDMR VMMAYELFSM WQNLGEHKIH FIPGMIGPFL GVTLVPQPEV RNIMIPIFHD MMDWEQRKNG NFKQVEAELI DKLDSMVSEG KGDESYRELF SLLTQLFGPY PSLLEKVEQE TWRETGISFV TSVTRLMERL LDYRDCMKGE ETENKKIGCT VNLMNFYKSE INKEEMYIRY IHKLCDMHLQ AENYTEAAFT LLLYCELLQW EDRPLREFLH YPSQTEWQRK EGLCRKIIHY FNKGKSWEFG IPLCRELACQ YESLYDYQSL SWIRKMEASY YDNIMEQQRL EPEFFRVGFY GRKFPFFLRN KEYVCRGHDY ERLEAFQQRM LSEFPQAVAM QHPNHPDDAI LQCDAQYLQI YAVTPIPDYV DVLQMDRVPD RVKSFYRVNN VRKFRYDRPF HKGPKDKENE FKSLWIERTT LTLTHSLPGI SRWFEVERRE LVEVSPLENA IQVVENKNQE LRSLISQYQH KQVHGNINLL SMCLNGVIDA AVNGGIARYQ EAFFDKDYIN KHPGDAEKIT QLKELMQEQV HVLGVGLAVH EKFVHPEMRP LHKKLIDQFQ MMRASLYHEF PGLDKLSPAC SGTSTPRGNV LASHSPMSPE SIKMTHRHSP MNLMGTGRHS SSSLSSHASS EAGNMVMLGD GSMGDAPEDL YHHMQLAYPN PRYQGSVTNV SVLSSSQASP SSSSLSSTHS APSQMITSAP SSARGSPSLP DKYRHAREMM LLLPTYRDRP SSAMYPAAIL ENGQPPNFQR ALFQQVVGAC KPCSDPNLSV AEKGHYSLHF DAFHHPLGDT PPALPARTLR KSPLHPIPAS PTSPQSGLDG SNSTLSGSAS SGVSSLSESN FGHSSEAPPR TDTMDSMPSQ AWNADEDLEP PYLPVHYSLS ESAVLDSIKA QPCRSHSAPG CVIPQDPMDP PALPPKPYHP RLPALEHDEG VLLREETERP RGLHRKAPLP PGSAKEEQAR MAWEHGRGEQ //