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Volume 271, Number 46, Issue of November 15, 1996 pp. 29016-29022
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Mutational Analysis of the A-Kinase Anchoring Protein (AKAP)-binding Site on RII
CLASSIFICATION OF SIDE CHAIN DETERMINANTS FOR ANCHORING AND ISOFORM SELECTIVE ASSOCIATION WITH AKAPs

(Received for publication, July 3, 1996)

From The Vollum Institute, Oregon Health Sciences University, L-474, Portland, Oregon 97201-3098

Compartmentalization of the type II cAMP-dependent protein kinase is conferred by interaction of the regulatory subunit (RII) with -inase nchoring roteins (AKAPs). The AKAP-binding site involves amino-terminal residues on each RII protomer and is formed through dimerization. A site-directed mutagenesis strategy was utilized to assess the contribution of individual residues in either RII isoform, RII or RII, for interaction with various anchoring proteins. Substitution of long-chain or bulky hydrophobic groups (leucines or phenylalanines) for isoleucines at positions 3 and 5 in RII decreased AKAP-binding up to 24 ± 3 (n = 8)-fold, whereas introduction of valines had minimal effects. Replacement with hydrophilic residues (serine or asparigine) at both positions abolished AKAP binding. Mutation of proline 6 in RII reduced binding for four AKAPs (Ht31, MAP2, AKAP79, and AKAP95) from 2.3 to 20-fold (n = 4) whereas introduction of an additional proline at position 6 in RII increased or conferred binding toward these anchoring proteins. Therefore, we conclude that -branched side chains at positions 3 and 5 are favored determinants for AKAP-binding and prolines at positions 6 and 7 increase or stabilize RII interaction with selected anchoring proteins.

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