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J. Biol. Chem., Vol. 279, Issue 16, 15831-15840, April 16, 2004

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A Critical Intramolecular Interaction for Protein Kinase C Translocation^*

Deborah Schechtman, Madeleine L. Craske, Viktoria Kheifets, Tobias Meyer, Jack Schechtman, and Daria Mochly-Rosen¶

From the Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, California 94305 and the Instituto de Matemática Pura e Aplicada, Rio de Janeiro, RJ 22460-320, Brazil

Disruption of intramolecular interactions, translocation from one intracellular compartment to another, and binding to isozyme-specific anchoring proteins termed RACKs, accompany protein kinase C (PKC) activation. We hypothesized that in inactive PKC, the RACK-binding site is engaged in an intramolecular interaction with a sequence resembling its RACK, termed RACK. An amino acid difference between the RACK sequence in PKC and its homologous sequence in RACK constitutes a change from a polar non-charged amino acid (asparagine) in RACK to a polar charged amino acid (aspartate) in PKC. Here we show that mutating the aspartate to asparagine in PKC increased intramolecular interaction as indicated by increased resistance to proteolysis, and slower hormone- or PMA-induced translocation in cells. Substituting aspartate for a non-polar amino acid (alanine) resulted in binding to RACK without activators, in vitro, and increased translocation rate upon activation in cells. Mathematical modeling suggests that translocation is at least a two-step process. Together our data suggest that intramolecular interaction between the RACK site and RACK-binding site within PKC is critical and rate limiting in the process of PKC translocation.

Received for publication, September 27, 2003 , and in revised form, January 20, 2004.

^* This work was supported by Grant AA1117 from the National Institutes of Health (to D. M-R). 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.

^¶ To whom correspondence should be addressed: Dept. of Molecular Pharmacology, Stanford University School of Medicine, CCSR 3145, 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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