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J. Biol. Chem., Vol. 282, Issue 39, 28893-28903, September 28, 2007

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A Novel Interaction between Atrophin-interacting Protein 4 and -p21-activated Kinase-interactive Exchange Factor Is Mediated by an SH3 Domain^*

Jay M. Janz¹, Thomas P. Sakmar², and K. Christopher Min³

From the Laboratory of Molecular Biology and Biochemistry, The Rockefeller University, New York, New York 10021 and the Department of Neurology, Columbia University, New York, New York 10032

Cross-talk between G protein-coupled receptors and receptor tyrosine kinase signaling pathways is crucial to the efficient relay and integration of cellular information. Here we identify and define the novel binding interaction of the E3 ubiquitin ligase atrophin-interacting protein 4 (AIP4) with the GTP exchange factor -p21-activated kinase-interactive exchange factor (PIX). We demonstrate that this interaction is mediated in part by the PIX-SH3 domain binding to a proline-rich stretch of AIP4. Analysis of the interaction by isothermal calorimetry is consistent with a heterotrimeric complex with one AIP4-derived peptide binding to two PIX-SH3 domains. We determined the crystal structure of the PIX-SH3·AIP4 complex to 2.0-Å resolution. In contrast to the calorimetry results, the crystal structure shows a monomeric complex in which AIP4 peptide binds the PIX-SH3 domain as a canonical Class I ligand with an additional type II polyproline helix that makes extensive contacts with another face of PIX. Taken together, the novel interaction between AIP4 and PIX represents a new regulatory node for G protein-coupled receptor and receptor tyrosine kinase signal integration. Our structure of the PIX-SH3·AIP4 complex provides important insight into the mechanistic basis for PIX scaffolding of signaling components, especially those involved in cross-talk.

Received for publication, March 28, 2007 , and in revised form, June 29, 2007.

The atomic coordinates and structure factors (code 2P4R) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by the Allene Reuss Memorial Trust and the Howard Hughes Medical Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Formerly an Ellison Medical Foundation Senior Scholar.

³ Supported by NIH Grant K08-EY015540.

¹ Supported in part by National Institutes of Health (NIH) Grant T3ZEY007138. To whom correspondence should be addressed: The Rockefeller University, 1230 York Ave., Box 187, New York, NY 10021. Tel.: 212-327-8283; Fax: 212-327-7904; E-mail: jjanz{at}rockefeller.edu.

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