DOCK3_HUMAN
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 03-AUG-2022, entry version 156.
DE RecName: Full=Dedicator of cytokinesis protein 3;
DE AltName: Full=Modifier of cell adhesion;
DE AltName: Full=Presenilin-binding protein;
DE Short=PBP;
GN Name=DOCK3; Synonyms=KIAA0299, MOCA;
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 presenilin proteins PSEN1 and PSEN2. Interacts
CC with CRK (By similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC Q8IZD9; Q13017-1: ARHGAP5; NbExp=2; IntAct=EBI-1752361, EBI-25409992;
CC Q8IZD9; P46108: CRK; NbExp=2; IntAct=EBI-1752361, EBI-886;
CC Q8IZD9; P49639: HOXA1; NbExp=3; IntAct=EBI-1752361, EBI-740785;
CC Q8IZD9; P16333: NCK1; NbExp=3; IntAct=EBI-1752361, EBI-389883;
CC Q8IZD9; Q9H8W4: PLEKHF2; NbExp=3; IntAct=EBI-1752361, EBI-742388;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}.
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}.
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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_004947.4.
DR AlphaFoldDB; Q8IZD9; -.
DR SMR; Q8IZD9; -.
DR BioGRID; 108130; 61.
DR IntAct; Q8IZD9; 37.
DR STRING; 9606.ENSP00000266037; -.
DR GlyGen; Q8IZD9; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q8IZD9; -.
DR PhosphoSitePlus; Q8IZD9; -.
DR BioMuta; DOCK3; -.
DR DMDM; 32469734; -.
DR MassIVE; Q8IZD9; -.
DR MaxQB; Q8IZD9; -.
DR PaxDb; Q8IZD9; -.
DR PeptideAtlas; Q8IZD9; -.
DR PRIDE; Q8IZD9; -.
DR ProteomicsDB; 71332; -.
DR Antibodypedia; 46085; 88 antibodies from 19 providers.
DR DNASU; 1795; -.
DR Ensembl; ENST00000266037.10; ENSP00000266037.8; ENSG00000088538.13.
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 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 neXtProt; NX_Q8IZD9; -.
DR OpenTargets; ENSG00000088538; -.
DR Orphanet; 528084; Non-specific syndromic intellectual disability.
DR PharmGKB; PA27455; -.
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 PhylomeDB; Q8IZD9; -.
DR TreeFam; TF300423; -.
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 BioGRID-ORCS; 1795; 9 hits in 1071 CRISPR screens.
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 128 other tissues.
DR Genevisible; Q8IZD9; HS.
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: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:1903997; P:positive regulation of non-membrane spanning protein tyrosine kinase activity; 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; cd12048; SH3_DOCK3_B; 1.
DR Gene3D; 1.20.1270.350; -; 1.
DR Gene3D; 1.20.58.740; -; 1.
DR Gene3D; 1.25.40.410; -; 1.
DR Gene3D; 2.60.40.150; -; 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; IPR026791; DOCK.
DR InterPro; IPR026800; DOCK3.
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; IPR036028; SH3-like_dom_sf.
DR InterPro; IPR001452; SH3_domain.
DR PANTHER; PTHR45653; PTHR45653; 1.
DR PANTHER; PTHR45653:SF4; PTHR45653:SF4; 1.
DR Pfam; PF06920; DHR-2; 1.
DR Pfam; PF14429; DOCK-C2; 1.
DR Pfam; PF16172; DOCK_N; 1.
DR Pfam; PF07653; SH3_2; 1.
DR SMART; SM00326; SH3; 1.
DR SUPFAM; SSF48371; SSF48371; 1.
DR SUPFAM; SSF50044; SSF50044; 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; Reference proteome;
KW 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..1765
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1871..1920
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1964..1980
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1981..2005
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; unknown pathological
FT significance; dbSNP:rs199600118)"
FT /evidence="ECO:0000269|PubMed:30976111"
FT /id="VAR_081832"
FT VARIANT 1296
FT /note="K -> R (in NEDIDHA; unknown pathological
FT significance; dbSNP:rs201184598)"
FT /evidence="ECO:0000269|PubMed:30976111"
FT /id="VAR_081833"
FT VARIANT 1674
FT /note="M -> L (in NEDIDHA; unknown pathological
FT significance; 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
