Gershenson Anne, Gierasch Lila M, Pastore Annalisa, Radford Sheena E
Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA.
1] Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA. [2] Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts, USA.
Nat Chem Biol. 2014 Nov;10(11):884-91. doi: 10.1038/nchembio.1670.
Evolutionary pressure for protein function leads to unavoidable sampling of conformational states that are at risk of misfolding and aggregation. The resulting tension between functional requirements and the risk of misfolding and/or aggregation in the evolution of proteins is becoming more and more apparent. One outcome of this tension is sensitivity to mutation, in which only subtle changes in sequence that may be functionally advantageous can tip the delicate balance toward protein aggregation. Similarly, increasing the concentration of aggregation-prone species by reducing the ability to control protein levels or compromising protein folding capacity engenders increased risk of aggregation and disease. In this Perspective, we describe examples that epitomize the tension between protein functional energy landscapes and aggregation risk. Each case illustrates how the energy landscapes for the at-risk proteins are sculpted to enable them to perform their functions and how the risks of aggregation are minimized under cellular conditions using a variety of compensatory mechanisms.
蛋白质功能的进化压力导致不可避免地对有错误折叠和聚集风险的构象状态进行抽样。在蛋白质进化过程中，功能需求与错误折叠和/或聚集风险之间产生的矛盾日益明显。这种矛盾的一个结果是对突变敏感，即序列中只有细微的、可能具有功能优势的变化，就可能使脆弱的平衡朝着蛋白质聚集的方向倾斜。同样，通过降低控制蛋白质水平的能力或损害蛋白质折叠能力来增加易于聚集的物种的浓度，会增加聚集和疾病的风险。在这篇观点文章中，我们描述了一些典型例子，这些例子体现了蛋白质功能能量景观与聚集风险之间的矛盾。每个案例都说明了有风险的蛋白质的能量景观是如何塑造的，以使它们能够发挥其功能，以及在细胞条件下如何利用各种补偿机制将聚集风险降至最低。
