Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, 250 14th Street NW, Atlanta, GA 30318, USA.
Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22517-22. doi: 10.1073/pnas.1012820107. Epub 2010 Dec 13.
At the heart of protein-protein interactions are protein-protein interfaces where the direct physical interactions occur. By developing and applying an efficient structural alignment method, we study the structural similarity of representative protein-protein interfaces involving interactions between dimers. Even without structural similarity between individual monomers that form dimeric complexes, ∼90% of native interfaces have a close structural neighbor with similar backbone C(α) geometry and interfacial contact pattern. About 80% of the interfaces form a dense network, where any two interfaces are structurally related using a transitive set of at most seven intermediate interfaces. The degeneracy of interface space is largely due to the packing of compact, hydrogen-bonded secondary structure elements. This packing generates relatively flat interacting surfaces whose geometries are highly degenerate. Comparative study of artificial and native interfaces argues that the library of protein interfaces is close to complete and comprised of roughly 1,000 distinct interface types. In contrast, the number of possible quaternary structures of dimers is estimated to be about 10(4) times larger; thus, an experimentally determined database of all representative quaternary structures is not likely in the near future. Nevertheless, one could in principle exploit the completeness of protein interfaces to predict most dimeric quaternary structures. Finally, our results provide a structural explanation for the prevalence of promiscuous protein interactions. By side-chain packing adjustments, we illustrate how multiprotein specificity can be attained at a promiscuous interface.
蛋白质-蛋白质相互作用的核心是蛋白质-蛋白质界面，直接的物理相互作用发生在这些界面上。通过开发和应用一种有效的结构对齐方法，我们研究了涉及二聚体相互作用的代表性蛋白质-蛋白质界面的结构相似性。即使在形成二聚体复合物的单体之间没有结构相似性，大约 90%的天然界面也有一个具有相似的骨架 C(α)几何形状和界面接触模式的紧密结构近邻。大约 80%的界面形成了一个密集的网络，其中任何两个界面都可以使用最多七个中间界面的传递集来建立结构关系。界面空间的简并性主要是由于紧凑的氢键结合二级结构元素的堆积造成的。这种堆积产生了相对平坦的相互作用表面，其几何形状高度简并。对人工和天然界面的比较研究表明，蛋白质界面库已经接近完整，由大约 1000 种不同的界面类型组成。相比之下，二聚体的可能四级结构的数量估计要大 10(4)倍左右；因此，在不久的将来不太可能获得所有代表性四级结构的实验确定的数据库。然而，原则上可以利用蛋白质界面的完整性来预测大多数二聚体四级结构。最后，我们的结果为普遍存在的混杂蛋白相互作用提供了一个结构解释。通过侧链堆积调整，我们说明了如何在混杂界面上实现多蛋白特异性。
