疏水性棘輪能夠固定分子複合物
作者：
小柯機器人發布時間：2020/12/12 19:56:34
美國芝加哥大學Joseph W. Thornton研究團隊發現，疏水性棘輪能夠固定分子複合物。該項研究成果於2020年12月9日在線發表在《自然》雜誌上。
研究人員發現，一個疏水突變的棘輪能夠系統地盤繞分子複合物。通過將祖先蛋白質重建和生化分析應用於類固醇激素受體的進化，研究人員表明，保存了數億年的古老疏水性界面已經根深蒂固，因為該界面暴露於溶劑會降低蛋白質穩定性並導致聚集，即使界面對功能沒有可檢測到的貢獻。使用結構生物信息學，研究人員揭示出普遍的突變傾向能夠驅動位點掩埋在多聚體界面中，從而將疏水性取代積累到單體無法容忍的水平。
在包含數百個多聚體家族的資料庫中，大多數顯示出長期疏水性固定的特徵。因此，很可能許多蛋白質複合物會持續存在，因為簡單的類棘輪機制會在整個進化過程中使它們牢固化，即使它們在功能上是無用的。
據了解，大多數蛋白質組裝成多亞基複合物。這些複合物在進化過程中的持久性通常被解釋為自然選擇功能特性的結果，這些功能特性取決於多聚化，例如亞基間變構或做機械功的能力。但是，在許多複合物中，多聚並不能實現任何已知功能。另一種解釋是，如果積累的取代在多聚體中是中性而在單體中是有害的，則多聚體可能會持久。即使組裝本身不能增強生物學功能，純化選擇也將阻止其回復為未組裝形式。
附：英文原文
Title: A hydrophobic ratchet entrenches molecular complexes
Author: Georg K. A. Hochberg, Yang Liu, Erik G. Marklund, Brian P. H. Metzger, Arthur Laganowsky, Joseph W. Thornton
Issue&Volume: 2020-12-09
Abstract: Most proteins assemble into multisubunit complexes1. The persistence of these complexes across evolutionary time is usually explained as the result of natural selection for functional properties that depend on multimerization, such as intersubunit allostery or the capacity to do mechanical work2. In many complexes, however, multimerization does not enable any known function3. An alternative explanation is that multimers could become entrenched if substitutions accumulate that are neutral in multimers but deleterious in monomers; purifying selection would then prevent reversion to the unassembled form, even if assembly per se does not enhance biological function3,4,5,6,7. Here we show that a hydrophobic mutational ratchet systematically entrenches molecular complexes. By applying ancestral protein reconstruction and biochemical assays to the evolution of steroid hormone receptors, we show that an ancient hydrophobic interface, conserved for hundreds of millions of years, is entrenched because exposure of this interface to solvent reduces protein stability and causes aggregation, even though the interface makes no detectable contribution to function. Using structural bioinformatics, we show that a universal mutational propensity drives sites that are buried in multimeric interfaces to accumulate hydrophobic substitutions to levels that are not tolerated in monomers. In a database of hundreds of families of multimers, most show signatures of long-term hydrophobic entrenchment. It is therefore likely that many protein complexes persist because a simple ratchet-like mechanism entrenches them across evolutionary time, even when they are functionally gratuitous.
DOI: 10.1038/s41586-020-3021-2
Source: https://www.nature.com/articles/s41586-020-3021-2