National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20352-7. doi: 10.1073/pnas.1012999107. Epub 2010 Nov 3.
The main principles of protein-protein recognition are elucidated by the studies of homooligomers which in turn mediate and regulate gene expression, activity of enzymes, ion channels, receptors, and cell-cell adhesion processes. Here we explore oligomeric states of homologous proteins in various organisms to better understand the functional roles and evolutionary mechanisms of homooligomerization. We observe a great diversity in mechanisms controlling oligomerization and focus in our study on insertions and deletions in homologous proteins and how they enable or disable complex formation. We show that insertions and deletions which differentiate monomers and dimers have a significant tendency to be located on the interaction interfaces and about a quarter of all proteins studied and forty percent of enzymes have regions which mediate or disrupt the formation of oligomers. We suggest that relatively small insertions or deletions may have a profound effect on complex stability and/or specificity. Indeed removal of complex enabling regions from protein structures in many cases resulted in the complete or partial loss of stability. Moreover, we find that insertions and deletions modulating oligomerization have a lower aggregation propensity and contain a larger fraction of polar, charged residues, glycine and proline compared to conventional interfaces and protein surface. Most likely, these regions may mediate specific interactions, prevent nonspecific dysfunctional aggregation and preclude undesired interactions between close paralogs therefore separating their functional pathways. Last, we show how the presence or absence of insertions and deletions on interfaces might be of practical value in annotating protein oligomeric states.
蛋白质-蛋白质识别的主要原则是通过同源寡聚体的研究来阐明的，这些同源寡聚体反过来介导和调节基因表达、酶活性、离子通道、受体和细胞-细胞黏附过程。在这里，我们探索了各种生物体中同源蛋白的寡聚状态，以更好地理解同源寡聚化的功能作用和进化机制。我们观察到控制寡聚化的机制存在很大的多样性，我们的研究重点是同源蛋白中的插入和缺失，以及它们如何使或阻止复合物的形成。我们表明，区分单体和二聚体的插入和缺失有很大的倾向位于相互作用界面上，在所研究的所有蛋白质中有四分之一和百分之四十的酶具有介导或破坏寡聚体形成的区域。我们认为，相对较小的插入或缺失可能对复合物稳定性和/或特异性产生深远的影响。事实上，从蛋白质结构中去除复杂的形成区域，在许多情况下会导致完全或部分丧失稳定性。此外，我们发现调节寡聚化的插入和缺失具有较低的聚集倾向，并且与常规界面和蛋白质表面相比，含有更大比例的极性、带电残基、甘氨酸和脯氨酸。很可能，这些区域可能介导特定的相互作用，防止非特异性的功能失调聚集，并防止紧密的旁系同源物之间的不期望的相互作用，从而分离它们的功能途径。最后，我们展示了接口上插入和缺失的存在或缺失如何在注释蛋白质寡聚状态方面具有实际价值。
