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Science 21 December 2007:
Vol. 318. no. 5858, pp. 1923 - 1927
DOI: 10.1126/science.1147554
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Reports

Structure of G{alpha}q-p63RhoGEF-RhoA Complex Reveals a Pathway for the Activation of RhoA by GPCRs

Susanne Lutz,1* Aruna Shankaranarayanan,2,3* Cassandra Coco,2 Marc Ridilla,2{dagger} Mark R. Nance,2 Christiane Vettel,1 Doris Baltus,1 Chris R. Evelyn,4 Richard R. Neubig,4 Thomas Wieland,1{ddagger} John J. G. Tesmer2,4{ddagger}

The guanine nucleotide exchange factor p63RhoGEF is an effector of the heterotrimeric guanine nucleotide–binding protein (G protein) G{alpha}q and thereby links G{alpha}q-coupled receptors (GPCRs) to the activation of the small-molecular-weight G protein RhoA. We determined the crystal structure of the G{alpha}q-p63RhoGEF-RhoA complex, detailing the interactions of G{alpha}q with the Dbl and pleckstrin homology (DH and PH) domains of p63RhoGEF. These interactions involve the effector-binding site and the C-terminal region of G{alpha}q and appear to relieve autoinhibition of the catalytic DH domain by the PH domain. Trio, Duet, and p63RhoGEF are shown to constitute a family of G{alpha}q effectors that appear to activate RhoA both in vitro and in intact cells. We propose that this structure represents the crux of an ancient signal transduction pathway that is expected to be important in an array of physiological processes.

1 Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Maybachstrasse 14, D-68169 Mannheim, Germany.
2 Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109–2216, USA.
3 Department of Chemistry and Biochemistry, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712–0165, USA.
4 Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109–0632, USA.

* These authors contributed equally to this work.

{dagger} Present address: Department of Biological Sciences, Purdue University, 915 West State Street, West Lafayette, IN 47907, USA.

{ddagger} To whom correspondence should be addressed. E-mail: tesmerjj{at}umich.edu (J.J.G.T.); thomas.wieland{at}urz.uniheidelberg.de (T.W.)

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