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J. Biol. Chem., Vol. 282, Issue 6, 4113-4123, February 9, 2007

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Peptides Derived from the C2 Domain of Protein Kinase C (PKC) Modulate PKC Activity and Identify Potential Protein-Protein Interaction Surfaces^*

From the Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305

Peptides derived from protein kinase C (PKC) modulate its activity by interfering with critical protein-protein interactions within PKC and between PKC and PKC-binding proteins (Souroujon, M. C., and Mochly-Rosen, D. (1998) Nat. Biotechnol. 16, 919-924). We previously demonstrated that the C2 domain of PKC plays a critical role in these interactions. By focusing on PKC and using a rational approach, we then identified one C2-derived peptide that acts as an isozyme-selective activator and another that acts as a selective inhibitor of PKC. These peptides were used to identify the role of PKC in protection from cardiac and brain ischemic damage, in prevention of complications from diabetes, in reducing pain, and in protecting transplanted hearts. The efficacy of these two peptides led us to search for additional C2-derived peptides with PKC-modulating activities. Here we report on the activity of a series of 5-9-residue peptides that are derived from regions that span the length of the C2 domain of PKC. These peptides were tested for their effect on PKC activity in cells in vivo and in an ex vivo model of acute ischemic heart disease. Most of the peptides acted as activators of PKC, and a few peptides acted as inhibitors. PKC-dependent myristoylated alanine-rich C kinase substrate phosphorylation in PKC knock-out cells revealed that only a subset of the peptides were selective for PKC over other PKC isozymes. These PKC-selective peptides were also protective of the myocardium from ischemic injury, an PKC-dependent function (Liu, G. S., Cohen, M. V., Mochly-Rosen, D., and Downey, J. M. (1999) J. Mol. Cell. Cardiol. 31, 1937-1948), and caused selective translocation of PKC over other isozymes when injected systemically into mice. Examination of the structure of the C2 domain from PKC revealed that peptides with similar activities clustered into discrete regions within the domain. We propose that these regions represent surfaces of protein-protein interactions within PKC and/or between PKC and other partner proteins; some of these interactions are unique to PKC, and others are common to other PKC isozymes.

Received for publication, September 5, 2006 , and in revised form, November 20, 2006.

^* This work was supported by National Institutes of Health Grant HL52141 (to D. M.-R.) and a Stanford Bio-X fellowship (to R. B.). 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.

¹ These authors contributed equally to this work.

² The founder of KAI Pharmaceuticals, Inc., a company that plans to bring PKC regulators to the clinic. However, none of the work described in this study is based on or supported by the company. To whom correspondence should be addressed: Dept. of Chemical and Systems Biology, Stanford University School of Medicine, CCSR, Rm. 3145A, 269 Campus Dr., Stanford, CA 94305-5174. Tel.: 650-725-7720; Fax: 650-723-2253; E-mail: mochly{at}stanford.edu.

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