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Science 337 (6099): 1218-1222

Copyright © 2012 by the American Association for the Advancement of Science

Conformational Control of the Ste5 Scaffold Protein Insulates Against MAP Kinase Misactivation

Jesse G. Zalatan,1,* Scott M. Coyle,1,2,* Saravanan Rajan,4 Sachdev S. Sidhu,4 Wendell A. Lim1,3,{dagger}

Abstract: Cells reuse signaling proteins in multiple pathways, raising the potential for improper cross talk. Scaffold proteins are thought to insulate against such miscommunication by sequestering proteins into distinct physical complexes. We show that the scaffold protein Ste5, which organizes the yeast mating mitogen-activated protein kinase (MAPK) pathway, does not use sequestration to prevent misactivation of the mating response. Instead, Ste5 appears to use a conformation mechanism: Under basal conditions, an intramolecular interaction of the pleckstrin homology (PH) domain with the von Willebrand type A (VWA) domain blocks the ability to coactivate the mating-specific MAPK Fus3. Pheromone-induced membrane binding of Ste5 triggers release of this autoinhibition. Thus, in addition to serving as a conduit guiding kinase communication, Ste5 directly receives input information to decide if and when signal can be transmitted to mating output.

1 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA.
2 Program in Biological Sciences, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA.
3 Howard Hughes Medical Institute, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA.
4 Banting and Best Department of Medical Research, Department of Molecular Genetics, and the Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: lim{at}cmp.ucsf.edu


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