Studying protein folding in health and disease using biophysical approaches.
Studying protein folding in health and disease using biophysical approaches.
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使用生物物理方法研究健康和疾病中的蛋白质折叠
DOI：
10.1042/etls20200317
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发表时间：
2021-05-14
影响因子：
3.8
通讯作者：
Perrett S
中科院分区：
文献类型：
--
作者：
Zhang H;Gong W;Wu S;Perrett S
蛋白质折叠对于包括发育和健康衰老在内的正常生理学至关重要，并且该过程的失败与包括神经变性和癌症在内的疾病的病理学有关。早期的热力学和动力学研究基于试管中单个蛋白质的解折叠和重折叠平衡，提供了对蛋白质折叠基本原理的深入了解，尽管预测任何给定蛋白质将如何折叠的问题仍然没有解决。细胞内的蛋白质折叠是比分离的纯化蛋白质的折叠更复杂的问题，这是由于细胞环境内的复杂相互作用，包括蛋白质的翻译后修饰、细胞中大分子拥挤的存在以及细胞环境的变化，例如在癌症与正常细胞中。生物物理学方法的发展，包括荧光共振能量转移（FRET）和核磁共振（NMR）技术和细胞操作，包括显微注射和插入非规范氨基酸，允许在活细胞中的蛋白质折叠的研究。此外，生物物理技术，如单分子荧光光谱和光镊允许在单分子水平上的简化系统的研究。将细胞内技术与从单分子研究中获得的强大细节相结合，可以监测包括分子伴侣在内的不同细胞组分的影响，为我们提供对蛋白质折叠过程的全面了解。生物物理技术在蛋白质折叠研究中的应用使我们掌握了对抗癌症和其他与蛋白质构象或蛋白质-蛋白质相互作用有关的疾病的基本知识。
Protein folding is crucial for normal physiology including development and healthy aging, and failure of this process is related to the pathology of diseases including neurodegeneration and cancer. Early thermodynamic and kinetic studies based on the unfolding and refolding equilibrium of individual proteins in the test tube have provided insight into the fundamental principles of protein folding, although the problem of predicting how any given protein will fold remains unsolved. Protein folding within cells is a more complex issue than folding of purified protein in isolation, due to the complex interactions within the cellular environment, including post-translational modifications of proteins, the presence of macromolecular crowding in cells, and variations in the cellular environment, for example in cancer versus normal cells. Development of biophysical approaches including fluorescence resonance energy transfer (FRET) and nuclear magnetic resonance (NMR) techniques and cellular manipulations including microinjection and insertion of noncanonical amino acids has allowed the study of protein folding in living cells. Furthermore, biophysical techniques such as single-molecule fluorescence spectroscopy and optical tweezers allows studies of simplified systems at the single molecular level. Combining in-cell techniques with the powerful detail that can be achieved from single-molecule studies allows the effects of different cellular components including molecular chaperones to be monitored, providing us with comprehensive understanding of the protein folding process. The application of biophysical techniques to the study of protein folding is arming us with knowledge that is fundamental to the battle against cancer and other diseases related to protein conformation or protein–protein interactions.