Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA.
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
Structure. 2014 Jan 7;22(1):59-69. doi: 10.1016/j.str.2013.10.012. Epub 2013 Dec 5.
The regulatory (R) subunit is the cAMP receptor of protein kinase A. Following cAMP binding, the inactive PKA holoenzyme complex separates into two active catalytic (C) subunits and a cAMP-bound R dimer. Thus far, only monomeric R structures have been solved, which fell short in explaining differences of cAMP binding for the full-length protein as compared to the truncated R subunits. Here we solved a full-length R-dimer structure that reflects the biologically relevant conformation, and this structure agrees well with small angle X-ray scattering. An isoform-specific interface is revealed between the protomers. This interface acts as an intermolecular sensor for cAMP and explains the cooperative character of cAMP binding to the RIα dimer. Mutagenesis of residues on this interface not only leads to structural and biochemical changes, but is also linked to Carney complex disease.
调节（R）亚基是蛋白激酶 A 的 cAMP 受体。在 cAMP 结合后，无活性的 PKA 全酶复合物分离成两个有活性的催化（C）亚基和一个 cAMP 结合的 R 二聚体。到目前为止，仅解决了单体 R 结构，这不足以解释全长蛋白与截短的 R 亚基相比，cAMP 结合的差异。在这里，我们解决了一个全长度的 R-二聚体结构，它反映了生物学上相关的构象，并且这个结构与小角度 X 射线散射很好地吻合。在原聚体之间揭示了一个同种型特异性的界面。该界面作为 cAMP 的分子间传感器，并解释了 cAMP 结合到 RIα 二聚体的协同特征。该界面上残基的突变不仅导致结构和生化变化，而且还与卡尼复合征疾病有关。
