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

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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
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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