Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, MC 0654, La Jolla, CA 92093, USA.
Structure. 2010 Feb 10;18(2):155-66. doi: 10.1016/j.str.2009.12.012.
A-kinase anchoring proteins (AKAPs) regulate cyclic AMP-dependent protein kinase (PKA) signaling in space and time. Dual-specific AKAP 2 (D-AKAP2) binds to the dimerization/docking (D/D) domain of both RI and RII regulatory subunits of PKA with high affinity. Here we have determined the structures of the RIalpha D/D domain alone and in complex with D-AKAP2. The D/D domain presents an extensive surface for binding through a well-formed N-terminal helix, and this surface restricts the diversity of AKAPs that can interact. The structures also underscore the importance of a redox-sensitive disulfide in affecting AKAP binding. An unexpected shift in the helical register of D-AKAP2 compared to the RIIalpha:D-AKAP2 complex structure makes the mode of binding to RIalpha novel. Finally, the comparison allows us to deduce a molecular explanation for the sequence and spatial determinants of AKAP specificity.
蛋白激酶 A (PKA) 的锚定蛋白 (AKAPs) 在空间和时间上调节环腺苷酸依赖性蛋白激酶 (PKA) 信号。双特异性 AKAP2 (D-AKAP2) 以高亲和力结合 PKA 的 RI 和 RII 调节亚基的二聚体/对接 (D/D) 结构域。在此,我们确定了 RIalpha D/D 结构域及其与 D-AKAP2 复合物的结构。D/D 结构域通过一个形成良好的 N 端螺旋呈现出广泛的结合表面,该表面限制了可相互作用的 AKAP 的多样性。这些结构还强调了氧化还原敏感二硫键在影响 AKAP 结合中的重要性。与 RIIalpha:D-AKAP2 复合物结构相比,D-AKAP2 的螺旋登记的意外变化使得与 RIalpha 的结合方式具有新颖性。最后,这种比较使我们能够推断出 AKAP 特异性的序列和空间决定因素的分子解释。