Entropic contributions and the influence of the hydrophobic environment in promiscuous protein-protein association
Entropic contributions and the influence of the hydrophobic environment in promiscuous protein-protein association
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DOI：
10.1073/pnas.0800452105
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发表时间：
2008-05-27
影响因子：
11.1
通讯作者：
McCammon, J. Andrew
中科院分区：
文献类型：
--
作者：
Chang, Chia-en A.;McLaughlin, William A.;McCammon, J. Andrew
混杂蛋白使用相同的结合界面与几种不同的蛋白强烈相互作用的机制还不完全清楚。一个例子是蛋白激酶A(PKA)，它利用其对接/二聚结构域上的单个面与多个A-激酶锚定蛋白(AKAP)相互作用，将其定位于细胞的不同部分。在本研究中，研究了构型熵对AKAP蛋白HT31与PKA的RIIa调节亚基的D/D结构域结合的贡献。结果表明，相互作用的大部分构型熵损失是由于侧链的旋转态内的涨落减少所致。这一结果与普遍认为的近似值相反，即侧链可用的旋转异构态数量的减少构成了主要成分。进一步的分析表明，在疏水环境中，总构型熵与有利的、可替代的接触数之间存在直接的线性关系。D/D结构域的疏水结合口袋为AKAP多肽的侧链提供了替代的接触点，使它们能够采用不同的结合构象。结合构象的增加提供了结合熵的增加，从而提供了结合亲和力的增加。我们推断，混杂蛋白的一般策略是在其界面提供替代接触点，以增加结合亲和力，同时保留与多个伙伴结合所需的可塑性。对理解和治疗使用混杂蛋白质相互作用的疾病的意义进行了讨论。
The mechanisms by which a promiscuous protein can strongly interact with several different proteins using the same binding interface are not completely understood. An example is protein kinase A (PKA), which uses a single face on its docking/dimerization domain to interact with multiple A-kinase anchoring proteins (AKAP) that localize it to different parts of the cell. In the current study, the configurational entropy contributions to the binding between the AKAP protein HT31 with the D/D domain of RII a-regulatory subunit of PKA were examined. The results show that the majority of configurational entropy loss for the interaction was due to decreased fluctuations within rotamer states of the side chains. The result is in contrast to the widely held approximation that the decrease in the number of rotamer states available to the side chains forms the major component. Further analysis showed that there was a direct linear relationship between total configurational entropy and the number of favorable, alternative contacts available within hydrophobic environments. The hydrophobic binding pocket of the D/D domain provides alternative contact points for the side chains of AKAP peptides that allow them to adopt different binding conformations. The increase in binding conformations provides an increase in binding entropy and hence binding affinity. We infer that a general strategy for a promiscuous protein is to provide alternative contact points at its interface to increase binding affinity while the plasticity required for binding to multiple partners is retained. Implications are discussed for understanding and treating diseases in which promiscuous protein interactions are used.