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J. Biol. Chem., Vol. 280, Issue 42, 35521-35527, October 21, 2005

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The Conformationally Dynamic C Helix of the RI Subunit of Protein Kinase A Mediates Isoform-specific Domain Reorganization upon C Subunit Binding^*

Dominico Vigil1, Donald K. Blumenthal, Susan S. Taylor, and Jill Trewhella¶2

From the Department of Chemistry and Biochemistry and Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California 92037 and the Departments of Pharmacology and Toxicology, Biochemistry, and ^¶Chemistry, University of Utah, Salt Lake City, Utah 84112

Different isoforms of the full-length protein kinase A (PKA) regulatory subunit homodimer (R₂) and the catalytic (C) subunit-bound holoenzyme (R₂C₂) have very different global structures despite similar molecular weights and domain organization within their primary sequences. To date, it has been the linker sequence between the R subunit dimerization/docking domain and cAMP-binding domain A that has been implicated in modulating domain interactions to give rise to these differences in global structure. The small angle solution scattering data presented here for three different isoforms of PKA heterodimer (R-C) complexes reveal a role for another conformationally dynamic sequence in modulating inter-subunit and domain interactions, the C helix that connects the cAMP-binding domains A and B of the R subunit. The R-C heterodimer complexes studied here were each formed with a monomeric N-terminal deletion mutant of the R subunit (R) that contains the inhibitor sequence and both cAMP-binding domains. The scattering data show that type II and type II R-C heterodimers are relatively compact and globular, with the C subunit contacting the inhibitor sequence and both cAMP-binding domains. In contrast, the type I heterodimer is significantly more extended, with the C subunit interacting with the inhibitor sequence and cAMP-binding domain A, whereas domain B extends out such that its surface is almost completely solvent exposed. These data implicate the C helix of RI in modulating isoform-specific interdomain communication in the PKA holoenzyme, adding another layer of structural complexity to our understanding of signaling dynamics in this multisubunit, multidomain protein kinase.

Received for publication, June 21, 2005 , and in revised form, August 17, 2005.

^* This work was supported in part by a grant from the U. S. Dept. of Energy Office of Science in support of the Oak Ridge Center for Structural Molecular Biology (to J. T.) and National Institutes of Health Grant GM34921 (to S. S. 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 Supported by National Institutes of Health Supplement Grant GM34921-19A1.

² To whom correspondence should be addressed: Dept. of Chemistry, 315 S. 1400 East, Rm. 1124 HEB, University of Utah, Salt Lake City, UT 84112. Tel.: 801-585-9328; Fax: 801-581-8433; E-mail: Jill.Trewhella{at}chemistry.utah.edu.

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