4.6 Article

Multiple Factors Confer Specific Cdc42 and Rac Protein Activation by Dedicator of Cytokinesis (DOCK) Nucleotide Exchange Factors

Journal

JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 28, Pages 25341-25351

Publisher

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.236455

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Funding

  1. Cancer Research UK

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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 (DOCKDHR2). Although the molecular basis for DOCKDHR2-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.

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