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Structural insights into formation of an active signaling complex between Rac and phospholipase C gamma 2

DOI: 10.1016/j.molcel.2009.02.023 DOI Help
PMID: 19394299 PMID Help

Authors: Tom D. Bunney (The Institute of Cancer Research) , Olaniyi Opaleye (The Institute of Cancer Research) , Petra Vatter (The Institute of Cancer Research) , Rhona W. Baxendale (The Institute of Cancer Research) , Claudia Walliser (The Institute of Cancer Research) , K.aty L. Everett (The Institute of Cancer Research) , Michelle B. Josephs (The Institute of Cancer Research) , Carolin Christow (The Institute of Cancer Research) , Fernando Rodriquez-lima (The Institute of Cancer Research) , S. Mark Roe (The Institute of Cancer Research) , Peter Gierschik (University of Ulm Medical Center) , Laurence H. Pearl (The Institute of Cancer Research) , Matilda Katan (The Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Cell , VOL 34 (2) , PAGES 223 - 33

State: Published (Approved)
Published: April 2009

Abstract: Rho family GTPases are important cellular switches and control a number of physiological functions. Understanding the molecular basis of interaction of these GTPases with their effectors is crucial in understanding their functions in the cell. Here we present the crystal structure of the complex of Rac2 bound to the split pleckstrin homology (spPH) domain of phospholipase C-?2 (PLC?2). Based on this structure, we illustrate distinct requirements for PLC?2 activation by Rac and EGF and generate Rac effector mutants that specifically block activation of PLC?2, but not the related PLC?2 isoform. Furthermore, in addition to the complex, we report the crystal structures of free spPH and Rac2 bound to GDP and GTP?S. These structures illustrate a mechanism of conformational switches that accompany formation of signaling active complexes and highlight the role of effector binding as a common feature of Rac and Cdc42 interactions with a variety of effectors.

Journal Keywords: Binding; Crystallography; X-Ray; Enzyme; Epidermal; Humans; Models; Molecular; Phospholipase; Protein; Tertiary; Sequence; Substrate; Thermodynamics; rac GTP-Binding Proteins

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography

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