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J. Biol. Chem., Vol. 283, Issue 28, 19511-19520, July 11, 2008

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Substrate Discrimination among Mitogen-activated Protein Kinases through Distinct Docking Sequence Motifs^*

Douglas L. Sheridan¹, Yong Kong, Sirlester A. Parker, Kevin N. Dalby^¶2, and Benjamin E. Turk³

From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, the Bioinformatics Resource, W. M. Keck Foundation Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, Connecticut 06520, and the ^¶Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin, Texas 78712

Mitogen-activated protein kinases (MAPKs) mediate cellular responses to a wide variety of extracellular stimuli. MAPK signal transduction cascades are tightly regulated, and individual MAPKs display exquisite specificity in recognition of their target substrates. All MAPK family members share a common phosphorylation site motif, raising questions as to how substrate specificity is achieved. Here we describe a peptide library screen to identify sequence requirements of the DEF site (docking site for ERK FXF), a docking motif separate from the phosphorylation site. We show that MAPK isoforms recognize DEF sites with unique sequences and identify two key residues on the MAPK that largely dictate sequence specificity. Based on these observations and computational docking studies, we propose a revised model for MAPK interaction with substrates containing DEF sites. Variations in DEF site sequence requirements provide one possible mechanism for encoding complex target specificity among MAPK isoforms.

Received for publication, February 8, 2008 , and in revised form, May 14, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM079498 (to B. E. T.) and GM59802 (to K. N. D.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Methods and Figs. 1 and 2.

¹ Supported by National Institutes of Health Training Grant T32 CA009085-33.

² Recipient of Welch Foundation Grant F-1390.

³ To whom correspondence should be addressed: Dept. of Pharmacology, Yale University School of Medicine, P. O. Box 208066, 333 Cedar St., New Haven, CT 06520. Tel.: 203-737-2494; Fax: 203-785-7670; E-mail: ben.turk{at}yale.edu.

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