When proteins evolve new activity, a concomitant decrease in stability is often observed because the mutations that confer new activity can destabilize the native fold. In the conventional model of protein evolution, reduced stability is considered a purely deleterious cost of molecular innovation because unstable proteins are prone to aggregation and are sensitive to environmental stressors. However, recent work has revealed that nonnative, often unstable protein conformations play an important role in mediating evolutionary transitions, raising the question of whether instability can itself potentiate the evolution of new activity. We explored this question in a bacteriophage receptor-binding protein during host-range evolution. We studied the properties of the receptor-binding protein of bacteriophage λ before and after host-range evolution and demonstrated that the evolved protein is relatively unstable and may exist in multiple conformations with unique receptor preferences. Through a combination of structural modeling and in vitro oligomeric state analysis, we found that the instability arises from mutations that interfere with trimer formation. This study raises the intriguing possibility that protein instability might play a previously unrecognized role in mediating host-range expansions in viruses.

中文翻译：

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病毒受体结合蛋白通过导致三聚体不稳定性和功能异质性的突变进化出新功能

当蛋白质进化出新的活性时，通常会观察到稳定性随之下降，因为赋予新活性的突变可能会破坏天然折叠的稳定性。在蛋白质进化的传统模型中，稳定性降低被认为是分子创新的纯粹有害成本，因为不稳定的蛋白质容易聚集并且对环境压力敏感。然而，最近的研究表明，非天然的、通常不稳定的蛋白质构象在介导进化转变中发挥着重要作用，这就提出了一个问题：不稳定本身是否可以增强新活性的进化。我们在宿主范围进化过程中的噬菌体受体结合蛋白中探索了这个问题。我们研究了噬菌体λ受体结合蛋白在宿主范围进化前后的特性，并证明进化后的蛋白相对不稳定，可能以具有独特受体偏好的多种构象存在。通过结构建模和体外寡聚状态分析的结合，我们发现不稳定是由干扰三聚体形成的突变引起的。这项研究提出了一种有趣的可能性，即蛋白质不稳定性可能在介导病毒宿主范围扩张方面发挥着以前未被认识到的作用。