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疏水性棘轮能够固定分子复合物
2020-12-12 19:56

美国芝加哥大学Joseph W. Thornton研究团队发现,疏水性棘轮能够固定分子复合物。该项研究成果于2020年12月9日在线发表在《自然》杂志上。

研究人员发现,一个疏水突变的棘轮能够系统地盘绕分子复合物。通过将祖先蛋白质重建和生化分析应用于类固醇激素受体的进化,研究人员表明,保存了数亿年的古老疏水性界面已经根深蒂固,因为该界面暴露于溶剂会降低蛋白质稳定性并导致聚集,即使界面对功能没有可检测到的贡献。使用结构生物信息学,研究人员揭示出普遍的突变倾向能够驱动位点掩埋在多聚体界面中,从而将疏水性取代积累到单体无法容忍的水平。

在包含数百个多聚体家族的数据库中,大多数显示出长期疏水性固定的特征。因此,很可能许多蛋白质复合物会持续存在,因为简单的类棘轮机制会在整个进化过程中使它们牢固化,即使它们在功能上是无用的。

据了解,大多数蛋白质组装成多亚基复合物。这些复合物在进化过程中的持久性通常被解释为自然选择功能特性的结果,这些功能特性取决于多聚化,例如亚基间变构或做机械功的能力。但是,在许多复合物中,多聚并不能实现任何已知功能。另一种解释是,如果积累的取代在多聚体中是中性而在单体中是有害的,则多聚体可能会持久。即使组装本身不能增强生物学功能,纯化选择也将阻止其回复为未组装形式。

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

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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