Author:
Lu Tsan-Wen,Wu Jian,Aoto Phillip C.,Weng Jui-Hung,Ahuja Lalima G.,Sun Nicholas,Cheng Cecilia Y.,Zhang Ping,Taylor Susan S.
Abstract
Protein kinase A (PKA) holoenzyme, comprised of a cAMP-binding regulatory (R)-subunit dimer and 2 catalytic (C)-subunits, is the master switch for cAMP-mediated signaling. Of the 4 R-subunits (RIα, RIβ, RIIα, RIIβ), RIα is most essential for regulating PKA activity in cells. Our 2 RIα2C2holoenzyme states, which show different conformations with and without ATP, reveal how ATP/Mg2+functions as a negative orthosteric modulator. Biochemical studies demonstrate how the removal of ATP primes the holoenzyme for cAMP-mediated activation. The opposing competition between ATP/cAMP is unique to RIα. In RIIβ, ATP serves as a substrate and facilitates cAMP-activation. The isoform-specific RI-holoenzyme dimer interface mediated by N3A–N3A′ motifs defines multidomain cross-talk and an allosteric network that creates competing roles for ATP and cAMP. Comparisons to the RIIβ holoenzyme demonstrate isoform-specific holoenzyme interfaces and highlights distinct allosteric mechanisms for activation in addition to the structural diversity of the isoforms.
Funder
HHS | NIH | National Institute of General Medical Sciences
HHS | NIH | National Cancer Institute
Taiwan MOE scholarship
Publisher
Proceedings of the National Academy of Sciences
Cited by
28 articles.
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