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J. Biol. Chem., Vol. 281, Issue 33, 23932-23944, August 18, 2006

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Regulation of AKAP-Membrane Interactions by Calcium^*

Jiangchuan Tao, Elena Shumay, Stuart McLaughlin, Hsien-yu Wang, and Craig C. Malbon¹

From the Departments of Pharmacology and Physiology and Biophysics, School of Medicine, Heath Sciences Center, State University of New York, Stony Brook, New York 11794-8651

The AKAP gravin is a scaffold for protein kinases, phosphatases, and adaptor molecules obligate for resensitization and recycling of ₂-adrenergic receptors. Gravin binds to the receptor through well characterized protein-protein interactions. These interactions are facilitated 1000-fold when gravin is anchored to the cytoplasmic leaflet of the plasma membrane. Although the N-terminal region (550 residues) is highly negatively charged and probably natively unfolded, it could anchor gravin to the inner leaflet through hydrophobic insertion of its N-terminal myristate and electrostatic binding of three short positively charged domains (PCDs). Loss of the site of N-myristoylation was found to affect neither AKAP macro-scopic localization nor AKAP function. Synthetic peptides corresponding to PCD1-3 bound in vitro to unilamellar phospholipid vesicles with high affinity, a binding reversed by calmodulin in the presence of Ca²⁺. In vivo gravin localization is regulated by intracellular Ca²⁺, a function mapping to the N terminus of the protein harboring PCD1, PCD2, and PCD3. Mutation of any two PCDs eliminates membrane association of the non-myristoylated gravin, the sensitivity to Ca²⁺/calmodulin, and the ability of this scaffold to catalyze receptor resensitization and recycling.

Received for publication, February 24, 2006 , and in revised form, June 7, 2006.

^* This work was supported by United States Public Health Service Grants (DK25410 (to C. C. M.), GM024971 (to S. M.), and GM69375 (to H. Y. W.)) from the National Institutes of Health as well as supported by institutional National Research Service Award (T32 DK007521) from the NIDDK, National Institutes of Health (to J. T.). 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 To whom correspondence should be addressed: Pharmacology-HSC, SUNY/Stony Brook, Stony Brook, NY 11794-8651. Tel.: 631-444-7873; Fax: 631-444-7696; E-mail: craig{at}pharm.sunysb.edu.

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