A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase
A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase
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DOI：
10.1016/j.molcel.2006.09.015
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发表时间：
2006-11-03
期刊：
影响因子：
16
通讯作者：
Taylor, Susan S.
中科院分区：
文献类型：
--
作者：
Kinderman, Francis S.;Kim, Choel;Taylor, Susan S.
激酶锚定蛋白（AKAP）通过使用与PKA调节（R）亚基的N-末端二聚化和对接（D/D）结构域对接的两亲性螺旋将PKA靶向至特定微结构域。为了理解特异性，我们解析了与RII alpha D/D结构域结合的双特异性AKAP D-AKAP 2的螺旋基序的晶体结构。1.6埃的结构揭示了这个动态的疏水对接位点是如何组装的。两个RII α原聚体的螺旋界面形成稳定的疏水对接槽。然后，一个原聚体的柔性N末端被募集到该位点，通过两个必需的异亮氨酸锚定到肽。另一个N端是无序的。这种不对称性为AKAP对接提供了更大的可能性。尽管在AKAP螺旋的N末端存在对RI α的强烈区分，但疏水沟区分RII α。Rim的凹槽中有一个空腔，可以接受大量的色氨酸，而RII alpha需要缬氨酸。
A kinase-anchoring proteins (AKAPs) target PKA to specific microdomains by using an amphipathic helix that docks to N-terminal dimerization and docking (D/D) domains of PKA regulatory (R) subunits. To understand specificity, we solved the crystal structure of the helical motif from D-AKAP2, a dual-specific AKAP, bound to the RII alpha D/D domain. The 1.6 angstrom structure reveals how this dynamic, hydrophobic docking site is assembled. A stable, hydrophobic docking groove is formed by the helical interface of two RII alpha protomers. The flexible N terminus of one protomer is then recruited to the site, anchored to the peptide through two essential isoleucines. The other N terminus is disordered. This asymmetry provides greater possibilities for AKAP docking. Although there is strong discrimination against RI alpha in the N terminus of the AKAP helix, the hydrophobic groove discriminates against RII alpha. Rim, with a cavity in the groove, can accept a bulky tryptophan, whereas RII alpha requires valine.