DOCK9
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDOCK9, ZIZ1, ZIZIMIN1, Dock9, dedicator of cytokinesis 9
External IDsOMIM: 607325 MGI: 106321 HomoloGene: 41026 GeneCards: DOCK9
Orthologs
SpeciesHumanMouse
Entrez

23348

105445

Ensembl

ENSG00000088387

ENSMUSG00000025558

UniProt

Q9BZ29

Q8BIK4

RefSeq (mRNA)

NM_001081039
NM_001128307
NM_001128308
NM_134074
NM_001347596

RefSeq (protein)

n/a

Location (UCSC)Chr 13: 98.79 – 99.09 MbChr 14: 121.78 – 122.04 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Dedicator of cytokinesis protein 9 (Dock9), also known as Zizimin1, is a large (~230 kDa) protein encoded in the human by the DOCK9 gene, involved in intracellular signalling networks.[5] It is a member of the DOCK-D subfamily of the DOCK family of guanine nucleotide exchange factors that function as activators of small G-proteins. Dock9 activates the small G protein Cdc42.

Discovery

Dock9 was discovered using an affinity proteomic approach designed to identify novel activators of the small G protein Cdc42 in fibroblasts.[6] Subsequent northern blot analysis revealed that Dock9 is expressed primarily in the brain, heart, skeletal muscle, kidney, placenta and lung. Lower levels were detected in the colon, thymus, liver, small intestine and in leukocytes from peripheral blood.

Structure and function

Dock9 shares a similar structure of two core domains (known as DHR1 and DHR2), which are shared by all DOCK family members. The C-terminal DHR2 domain functions as an atypical GEF domain for small G proteins (see Dock180: structure and function) and the DHR1 domain is known, in some DOCK-A/B/C subfamily proteins, to be involved in their recruitment to the plasma membrane. Unlike DOCK-A/B/C proteins DOCK-D proteins (including Dock9) contain an N-terminal pleckstrin homology (PH) domain that mediates their recruitment to the membrane.[7] Dock9, along with other DOCK-C/D subfamily members, can activate Cdc42 in vitro and in vivo via its DHR2 domain.[6] However, Dock9 adopts an autoinhibitory conformation that masks the DHR2 domain in its resting state.[7] The mechanism by which this autoinhibition is overcome is still unclear although in some other DOCK proteins, which also undergo autoinhibition, it requires an interaction with adaptor proteins such as ELMO.[8][9] Dock9 has also been reported to dimerise, under resting conditions, via its DHR2 domains and this study suggests that other DOCK family proteins may also behave in the same way.[10] Recent analysis of a chromosomal region associated with susceptibility to bipolar disorder revealed that single nucleotide polymorphisms in the DOCK9 gene contribute to the risk and severity of this condition.[11]


References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000088387 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000025558 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: DOCK9 dedicator of cytokinesis 9".
  6. 1 2 Meller N, Irani-Tehrani M, Kiosses WB, et al. (September 2002). "Zizimin1, a novel Cdc42 activator, reveals a new GEF domain for Rho proteins". Nat. Cell Biol. 4 (9): 639–47. doi:10.1038/ncb835. PMID 12172552. S2CID 24507862.
  7. 1 2 Meller N, Westbrook MJ, Shannon JD, et al. (January 2008). "Function of the N-terminus of zizimin1: autoinhibition and membrane targeting". Biochem. J. 409 (2): 525–33. doi:10.1042/BJ20071263. PMC 2740492. PMID 17935486.
  8. ↑ Lu M, Kinchen JM, Rossman KL, et al. (August 2004). "PH domain of ELMO functions in trans to regulate Rac activation via Dock180". Nat. Struct. Mol. Biol. 11 (8): 756–62. doi:10.1038/nsmb800. PMID 15247908. S2CID 125990.
  9. ↑ Lu M, Kinchen JM, Rossman KL, et al. (February 2005). "A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs". Curr. Biol. 15 (4): 371–77. doi:10.1016/j.cub.2005.01.050. PMID 15723800.
  10. ↑ Meller N, Irani-Tehrani M, Ratnikov BI, et al. (September 2004). "The novel Cdc42 guanine nucleotide exchange factor, zizimin1, dimerizes via the Cdc42-binding CZH2 domain". J. Biol. Chem. 279 (36): 37470–76. doi:10.1074/jbc.M404535200. PMID 15247287.
  11. ↑ Detera-Wadleigh SD, Liu CY, Maheshwari M, et al. (October 2007). "Sequence variation in DOCK9 and heterogeneity in bipolar disorder". Psychiatr. Genet. 17 (5): 274–86. doi:10.1097/YPG.0b013e328133f352. PMID 17728666. S2CID 7102906.

Further reading


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