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Activation of Rho GTPases by DOCK Exchange Factors Is Mediated by a Nucleotide Sensor

DOI: 10.1126/science.1174468 DOI Help
PMID: 19745154 PMID Help

Authors: Jingjie Yang (Institute of Cancer Research) , Ziguo Zhang (Institute of Cancer Research) , Mark Roe (Institute of Cancer Research,) , Christopher J. Marshall (Institute of Cancer Research) , David Barford (Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science , VOL 325

State: Published (Approved)
Published: September 2009

Abstract: Activation of Rho guanosine triphosphatases (GTPases) to the guanine triphosphate (GTP)–bound state is a critical event in their regulation of the cytoskeleton and cell signaling. Members of the DOCK family of guanine nucleotide exchange factors (GEFs) are important activators of Rho GTPases, but the mechanism of activation by their catalytic DHR2 domain is unknown. Through structural analysis of DOCK9-Cdc42 complexes, we identify a nucleotide sensor within the ?10 helix of the DHR2 domain that contributes to release of guanine diphosphate (GDP) and then to discharge of the activated GTP-bound Cdc42. Magnesium exclusion, a critical factor in promoting GDP release, is mediated by a conserved valine residue within this sensor, whereas binding of GTP-Mg2+ to the nucleotide-free complex results in magnesium-inducing displacement of the sensor to stimulate discharge of Cdc42-GTP. These studies identify an unusual mechanism of GDP release and define the complete GEF catalytic cycle from GDP dissociation followed by GTP binding and discharge of the activated GTPase.

Journal Keywords: Catalytic; Crystallography; X-Ray; Enzyme; Guanine; Guanosine; Guanosine; Humans; Magnesium; Models; Molecular; Protein; Secondary; Protein; Tertiary; cdc42 GTP-Binding Protein

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography

Added On: 12/10/2009 12:42

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