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The life of proteins under mechanical force
Chemical Society Reviews ( IF 46.2 ) Pub Date : 2018-02-23 00:00:00 , DOI: 10.1039/c7cs00820a
Jörg Schönfelder 1, 2, 3, 4, 5 , Alvaro Alonso-Caballero 1, 2, 3 , David De Sancho 1, 2, 3, 6, 7 , Raul Perez-Jimenez 1, 2, 3, 6, 7
Affiliation  

Although much of our understanding of protein folding comes from studies of isolated protein domains in bulk, in the cellular environment the intervention of external molecular machines is essential during the protein life cycle. During the past decade single molecule force spectroscopy techniques have been extremely useful to deepen our understanding of these interventional molecular processes, as they allow for monitoring and manipulating mechanochemical events in individual protein molecules. Here, we review some of the critical steps in the protein life cycle, starting with the biosynthesis of the nascent polypeptide chain in the ribosome, continuing with the folding supported by chaperones and the translocation into different cell compartments, and ending with proteolysis in the proteasome. Along these steps, proteins experience molecular forces often combined with chemical transformations, affecting their folding and structure, which are measured or mimicked in the laboratory by the application of force with a single molecule apparatus. These mechanochemical reactions can potentially be used as targets for fighting against diseases. Inspired by these insightful experiments, we devise an outlook on the emerging field of mechanopharmacology, which reflects an alternative paradigm for drug design.

中文翻译:

机械力作用下蛋白质的寿命

尽管我们对蛋白质折叠的大部分理解来自大量对分离的蛋白质结构域的研究,但在细胞环境中,外部分子机器的干预在蛋白质生命周期中至关重要。在过去的十年中,单分子力光谱技术对于加深我们对这些介入性分子过程的理解非常有用,因为它们允许监视和操纵单个蛋白质分子中的机械化学事件。在这里,我们回顾了蛋白质生命周期中的一些关键步骤,从核糖体中新生多肽链的生物合成开始,继续由伴侣蛋白支持的折叠和易位到不同的细胞室中,最后以蛋白酶体中的蛋白水解作用结束。按照这些步骤,蛋白质经受的分子力通常与化学转化结合在一起,从而影响其折叠和结构,而折叠和结构在实验室中是通过使用单分子仪器施加力来测量或模拟的。这些机械化学反应可以潜在地用作抗击疾病的靶标。受到这些有洞察力的实验的启发,我们对机械药理学的新兴领域进行了展望,这反映了药物设计的另一范式。
更新日期:2018-02-23
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