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]
^ abMeller 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. PMID12172552.
^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. PMID15247908.
^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. PMID15723800.
^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. PMID15247287.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^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. PMID17728666.
