Multiple Factors Confer Specific Cdc42 and Rac Protein Activation by Dedicator of Cytokinesis (DOCK) Nucleotide Exchange Factors
Kulkarni, K., Yang, J., Zhang, Z. G., Barford, D.
(2011)
Multiple Factors Confer Specific Cdc42 and Rac Protein Activation by Dedicator of Cytokinesis (DOCK) Nucleotide Exchange Factors.
JOURNAL OF BIOLOGICAL CHEMISTRY, 286 (28).
pp. 25341-25351.
ISSN 0021-9258
Full text not available from this repository.
Abstract
DOCK (dedicator of cytokinesis) guanine nucleotide exchange factors (GEFs) activate the Rho-family GTPases Rac and Cdc42 to control cell migration, morphogenesis, and phagocytosis. The DOCK A and B subfamilies activate Rac, whereas the DOCK D subfamily activates Cdc42. Nucleotide exchange is catalyzed by a conserved DHR2 domain (DOCK(DHR2)). Although the molecular basis for DOCK(DHR2)-mediated GTPase activation has been elucidated through structures of a DOCK9(DHR2)-Cdc42 complex, the factors determining recognition of specific GTPases are unknown. To understand the molecular basis for DOCK-GTPase specificity, we have determined the crystal structure of DOCK2(DHR2) in complex with Rac1. DOCK2(DHR2) and DOCK9(DHR2) exhibit similar tertiary structures and homodimer interfaces and share a conserved GTPase-activating mechanism. Multiple structural differences between DOCK2(DHR2) and DOCK9(DHR2) account for their selectivity toward Rac1 and Cdc42. Key determinants of selectivity of Cdc42 and Rac for their cognate DOCK(DHR)2 are a Phe or Trp residue within beta 3 (residue 56) and the ability of DOCK proteins to exploit differences in the GEF-induced conformational changes of switch 1 dependent on a divergent residue at position 27. DOCK proteins, therefore, differ from DH-PH GEFs that select their cognate GTPases through recognition of structural differences within the beta 2/beta 3 strands.
Item Type: | Article |
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Authors (ICR Faculty only): | Barford, David |
All Authors: | Kulkarni, K., Yang, J., Zhang, Z. G., Barford, D. |
Additional Information: | ISI Document Delivery No.: 789WD Times Cited: 0 Cited Reference Count: 51 Kulkarni, Kiran Yang, Jing Zhang, Ziguo Barford, David Cancer Research UK This work was supported by a program grant from Cancer Research UK (to D.B.). Amer soc biochemistry molecular biology inc Bethesda |
Uncontrolled Keywords: | rho gtpases cytoskeletal reorganization crkii/dock180/rac pathway overlap extension structural basis cell-migration binding domain membrane family |
Research teams: | Closed research groups > Macromolecular Structure Laboratory - Barford Group |
Depositing User: | Barry Jenkins |
Date Deposited: | 04 Aug 2011 14:53 |
Last Modified: | 11 Sep 2014 14:19 |
URI: | http://publications.icr.ac.uk/id/eprint/10884 |
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