合成生物学 ›› 2022, Vol. 3 ›› Issue (3): 445-464.DOI: 10.12211/2096-8280.2022-013

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唐宇琦1,2, 叶松涛1,2, 刘嘉1,2, 张鑫1,2   

  1. 1.西湖大学理学院化学系,浙江 杭州 310030
    2.浙江西湖高等研究院,理学研究所,浙江 杭州 310024
  • 收稿日期:2022-02-12 修回日期:2022-05-07 出版日期:2022-06-30 发布日期:2022-07-13
  • 通讯作者: 张鑫
  • 作者简介:唐宇琦(1998 —),女,科研助理。研究方向是对体外蛋白质相分离的理解。E-mail: tangyuqi@westlake.edu.cn|张鑫(1978 —),男,教授,博士生导师。张鑫课题组聚焦于化学和生物的交叉领域,以“生物聚集体化学”为研究中心,瞄准此研究领域亟需解决的重要科学和技术问题,为基础研究和生物医药产业提供重要科学支持。E-mail: zhangxin@westlake.edu.cn

Molecular chaperones promote protein stability and evolution

Yuqi TANG1,2, Songtao YE1,2, Jia LIU1,2, Xin ZHANG1,2   

  1. 1.Department of Chemistry,School of Science,Westlake University,Hangzhou 310030,Zhejiang,China
    2.Institute of Natural Sciences,Westlake Institute for Advanced Study,Hangzhou 310024,Zhejiang,China
  • Received:2022-02-12 Revised:2022-05-07 Online:2022-06-30 Published:2022-07-13
  • Contact: Xin ZHANG



关键词: 蛋白质折叠, 边缘稳定性, 定向进化, 分子伴侣


Native proteins are only marginally stable. Therefore, a few mutations or slight perturbation in the environment could easily destroy their functional structures, causing them to misfold or even aggregate. The proteome is also believed to be marginally stable as the malfunction of a handful of proteins could rapidly overload the ubiquitin-protease network, threatening the integrity of the entire proteome. The disruption of proteostasis would render tremendous side effects including tumors and diseases. Extensive molecular machineries, such as heat shock proteins, are employed by cells to assist certain protein folding, salvage misfolded proteins, and break down protein aggregates. Owing to this fact, many natively occurred molecular chaperones have the potency to be engineered as stabilizers for the expression of aggregation-prone proteins both in vitro and in vivo, or into specialized disaggregates towards disease-related proteins. Remarkably, these modifications could be achieved with minor changes in the primary sequence of typical molecular chaperones, which are often proved to be single-site mutations. Instead of focusing on particular molecular chaperones, an up-regulation of the entire proteostasis network components is proved to be a viable strategy in maintaining protein homeostasis. Mutations could also render proteins to evolve new or improved functions in given environments, even though most mutations are detrimental. Both theoretical and experimental studies have found that extra thermodynamic stability could promote evolvability by allowing a protein's native structure and function to tolerate random mutations more robustly. Increased mutational tolerance allows proteins to evolve faster to adapt to new environments. Molecular chaperones are also found to serve as a buffering system, alleviating stability constraints, and rescuing deleterious mutations that could mediate new or improved functions. Hopefully, with the advancement in biotechnology and computational analysis, more studies that reveal influences of molecular chaperones on protein stability and evolvability can provide better insights into deciphering the relationship between protein structures and functions, as well as fundamental theories exploring the pathogenesis of protein-related diseases.

Key words: protein folding, marginal stability, directed evolution, molecular chaperones