Toward a better understanding of protein folding pathways.
Toward a better understanding of protein folding pathways.
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更好地了解蛋白质折叠途径。
DOI：
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发表时间：
1988
影响因子：
11.1
通讯作者：
T. Creighton
中科院分区：
文献类型：
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作者：
T. Creighton
对展开的蛋白质如何重新折叠成其天然三维结构的实验观察，与许多关于蛋白质折叠机制的流行理论形成了鲜明对比。现有的实验证据(忽略缓慢的顺式-反式多肽键异构化)基本上符合以下一般原理：在折叠条件下，未折叠的蛋白质分子在完全折叠之前在不同构象之间迅速平衡。这种快速的预折叠平衡有利于某些紧凑的构象，这些构象的自由能比其他展开的构象略低。一些受欢迎的构象对于高产的折叠是重要的。限速步骤发生在途径的后期，涉及到天然构象的高能、扭曲形式；似乎有一个单一的过渡态，几乎所有的分子都通过这个过渡态重新折叠。因此，蛋白质不是通过大量独立的途径组装的，折叠也不是由未折叠蛋白质中的成核事件启动的，紧随其后的是折叠结构的快速增长。已知的涉及二硫键形成的折叠路径遵循相同的一般原理。Scheraga等人提出的还原核糖核酸酶A的特殊折叠机制。(Scheraga，H.A.，Konishi，Y.，Rothwarf，D.M.&Mui，P.W.(1987)Proc.娜塔莉。阿卡德。SCI。美国84,5740-5744)被证明是由于实验缺陷、不正确的动力学分析以及未能考虑展开动力学的结果。
Experimental observations of how unfolded proteins refold to their native three-dimensional structures contrast with many popular theories of protein folding mechanisms. The available experimental evidence (ignoring slow cis-trans peptide bond isomerization) is largely consistent with the following general scheme: under folding conditions, unfolded protein molecules rapidly equilibrate between different conformations prior to complete refolding. This rapid prefolding equilibrium favors certain compact conformations that have somewhat lower free energies than the other unfolded conformations. Some of the favored conformations are important for productive folding. The rate-limiting step occurs late in the pathway and involves a high-energy, distorted form of the native conformation; there appears to be a single transition state through which essentially all molecules refold. Consequently, proteins are not assembled via a large number of independent pathways, nor is folding initiated by a nucleation event in the unfolded protein followed by rapid growth of the folded structure. The known folding pathways involving disulfide bond formation follow the same general principles. An exceptional folding mechanism for reduced ribonuclease A proposed by Scheraga et al. (Scheraga, H.A., Konishi, Y., Rothwarf, D.M. & Mui, P.W. (1987) Proc. Natl. Acad. Sci. USA 84, 5740-5744) is shown to result from experimental shortcomings, an incorrect kinetic analysis, and a failure to consider the kinetics of unfolding.