Tradeoff between stability and multispecificity in the design of promiscuous proteins.
Tradeoff between stability and multispecificity in the design of promiscuous proteins.
复制标题
DOI：
10.1371/journal.pcbi.1000627
复制
发表时间：
2009-12
影响因子：
4.3
通讯作者：
Shifman JM
中科院分区：
文献类型：
--
作者：
Fromer M;Shifman JM
天然蛋白质通常参与几种高度特异性的蛋白质-蛋白质相互作用。因此，它们在进化选择过程中受到多种相反力量的影响。为了发挥功能，这种多特异性蛋白质需要与每个相互作用伴侣保持稳定的复合物，同时保持对所有伴侣的亲和力。这种多特异性是如何通过自然进化获得的？为了回答这个令人信服的问题，我们研究了一种典型的多特异性蛋白质，钙调素（CaM），它已经进化到与数百种靶蛋白相互作用。从16个钙调素靶复合物的高分辨率结构开始，我们采用最先进的计算方法来预测100个最适合与每个钙调素靶相互作用的钙调素序列。然后，我们设计了与两个、三个和所有16个靶点的每种可能组合最兼容的CaM序列，产生了近70，000个低能量CaM序列。通过比较这些序列和它们的能量，我们可以深入了解大自然是如何设法在有利的相互作用能和多特异性之间找到妥协的。我们观察到，设计更多的合作伙伴，同时产生的钙调素序列，更好地匹配自然序列概况，从而强调了这种战略在自然界中的重要性。此外，我们表明，钙调素结合界面可以很好地划分为位置，是至关重要的所有钙调素-目标复合物的亲和力和那些被塑造，以提供相互作用的特异性。我们揭示了几个基本类别的序列水平的权衡，使这种蛋白质的滥交必要的妥协。我们还彻底量化了相互作用能量和多特异性之间的权衡，并发现促进看似竞争的相互作用只需要一个小的偏离最佳能量。我们的结论是，多特异性蛋白质已经进行了严格的优化过程，微调其序列与一组精确的目标相互作用，从而赋予其多种细胞功能。在自然界中，一些蛋白质比其他蛋白质更具社会性，与大量的伴侣相互作用。这些“混杂”蛋白质在细胞信号通路中发挥关键作用，其破坏可能导致癌症等疾病。这些蛋白质的氨基酸序列必须进化到最适合与所有天然伴侣的组合相互作用。然而，导致这种滥交的进化过程还没有完全理解。我们解决这个问题，通过预测氨基酸序列，将是最兼容的相互作用与每个合作伙伴本身和那些最兼容的结合多种蛋白质。我们发现，这两种类型的序列有很大的不同，后者更接近于混杂蛋白质的天然序列。我们还发现，混杂蛋白质包含某些区域，这些区域是与其所有伴侣相互作用所必需的，而其他区域则与每个特定的靶蛋白质进行特定的相互作用。我们分析了这些蛋白质结合多个合作伙伴所需的权衡，并发现只有一定程度的妥协通常是需要的，以允许看似对立的相互作用。我们的结论是，这里报道的模拟很好地模拟了与多个合作伙伴相关联的蛋白质的自然进化。
Natural proteins often partake in several highly specific protein-protein interactions. They are thus subject to multiple opposing forces during evolutionary selection. To be functional, such multispecific proteins need to be stable in complex with each interaction partner, and, at the same time, to maintain affinity toward all partners. How is this multispecificity acquired through natural evolution? To answer this compelling question, we study a prototypical multispecific protein, calmodulin (CaM), which has evolved to interact with hundreds of target proteins. Starting from high-resolution structures of sixteen CaM-target complexes, we employ state-of-the-art computational methods to predict a hundred CaM sequences best suited for interaction with each individual CaM target. Then, we design CaM sequences most compatible with each possible combination of two, three, and all sixteen targets simultaneously, producing almost 70,000 low energy CaM sequences. By comparing these sequences and their energies, we gain insight into how nature has managed to find the compromise between the need for favorable interaction energies and the need for multispecificity. We observe that designing for more partners simultaneously yields CaM sequences that better match natural sequence profiles, thus emphasizing the importance of such strategies in nature. Furthermore, we show that the CaM binding interface can be nicely partitioned into positions that are critical for the affinity of all CaM-target complexes and those that are molded to provide interaction specificity. We reveal several basic categories of sequence-level tradeoffs that enable the compromise necessary for the promiscuity of this protein. We also thoroughly quantify the tradeoff between interaction energetics and multispecificity and find that facilitating seemingly competing interactions requires only a small deviation from optimal energies. We conclude that multispecific proteins have been subjected to a rigorous optimization process that has fine-tuned their sequences for interactions with a precise set of targets, thus conferring their multiple cellular functions. In nature, some proteins are more social than others, interacting with a large number of partners. These “promiscuous” proteins play key roles in cellular signaling pathways whose disruption may lead to diseases such as cancer. The amino acid sequences of such proteins must have evolved to be optimal for combined interactions with all natural partners. However, the evolutionary process leading to this promiscuity is not fully understood. We address this subject by predicting amino acid sequences that would be most compatible for interaction with each partner on its own and those most compatible for binding multiple proteins. We find that these two types of sequences are substantially different, the latter more closely resembling the natural sequences of promiscuous proteins. We also find that promiscuous proteins contain certain regions that are necessary for interfacing with all of their partners, while other regions convey specific interactions with each particular target protein. We analyze the tradeoffs required for such proteins to bind multiple partners and find that only some degree of compromise is typically needed in order to permit interactions that are seemingly antagonistic. We conclude that the simulations reported here mimic well the natural evolution of proteins that associate with multiple partners.
登录
查看更多内容
天然蛋白质的稳定性和热适应性的正面设计。
影响因子：
4.3
作者：
Berezovsky, Igor N.;Zeldovich, Konstantin B.;Shakhnovich, Eugene I.
通讯作者：
Shakhnovich, Eugene I.
影响因子：
56.9
作者：
Dahiyat, BI;Mayo, SL
通讯作者：
Mayo, SL
DOI：
10.1073/pnas.0506124102
发表时间：
2005-09-06
影响因子：
11.1
作者：
Bolon, DN;Grant, RA;Sauer, RT
通讯作者：
Sauer, RT
影响因子：
64.8
作者：
Grigoryan, Gevorg;Reinke, Aaron W.;Keating, Amy E.
通讯作者：
Keating, Amy E.
影响因子：
56.9
作者：
Barabási, AL;Albert, R
通讯作者：
Albert, R