两种蛋白激酶 A RIα 全酶状态将 ATP 定义为一种同工型特异性的正构抑制剂，与变构激活剂 cAMP 竞争。
Two PKA RIα holoenzyme states define ATP as an isoform-specific orthosteric inhibitor that competes with the allosteric activator, cAMP.
机构信息
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093.
Department of Pharmacology, University of California San Diego, La Jolla, CA 92093.
出版信息
Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16347-16356. doi: 10.1073/pnas.1906036116. Epub 2019 Jul 30.
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 RIαC holoenzyme states, which show different conformations with and without ATP, reveal how ATP/Mg 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.
蛋白激酶 A（PKA）全酶由环腺苷酸（cAMP）结合调节（R）亚基二聚体和 2 个催化（C）亚基组成，是 cAMP 介导的信号转导的主开关。在 4 个 R 亚基（RIα、RIβ、RIIα、RIIβ）中，RIα 对调节细胞中的 PKA 活性最为重要。我们的 2 种 RIαC 全酶状态，分别显示有无 ATP 时的不同构象，揭示了 ATP/Mg 如何作为负变构调节剂发挥作用。生化研究表明，ATP 的去除如何使全酶为 cAMP 介导的激活做好准备。RIα 中的这种 ATP/cAMP 之间的反向竞争是独特的。在 RIIβ 中，ATP 作为底物并促进 cAMP 激活。由 N3A-N3A'基序介导的同工型特异性 RI 全酶二聚体界面定义了多域串扰和变构网络，为 ATP 和 cAMP 创造了竞争作用。与 RIIβ 全酶的比较表明同工型特异性全酶界面和独特的变构机制，除了同工型的结构多样性外，还可用于激活。
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