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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Integrating folding kinetics and protein function: Biphasic kinetics and dual binding specificity in a WW domain
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Integrating folding kinetics and protein function: Biphasic kinetics and dual binding specificity in a WW domain

机译：整合折叠动力学和蛋白质功能：WW域中的双相动力学和双重结合特异性

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摘要

Because of the association of beta-sheet formation with the initiation and propagation of amyloid diseases, model systems have been sought to further our understanding of this process. WW domains have been proposed as one such model system. Whereas the folding of the WW domains from human Yes-associated protein (YAP) and Pin have been shown to obey single-exponential kinetics, the folding of the WW domain from formin-binding protein (FBP) 28 has been shown to proceed via biphasic kinetics. From an analysis of free-energy landscapes from atomic-level molecular dynamics simulations, the biphasic folding kinetics observed in the FBP WW domain may be traced to the ability of this M domain to adopt two slightly different forms of packing in its hydrophobic core. This conformational change is propagated along the peptide backbone and affects the position of a tryptophan residue shown in other WW domains to play a key role in binding. The WW domains of Pin and YAP do not support more than one type of packing each, leading to monophasic folding kinetics. The ability of the FBP WW domain to assume two different types of packing may, in turn, explain the capacity of this WW domain to bind two classes of ligand, a property that is not shared by other WW domains. These findings lead to the hypothesis that lability with respect to conformations separated by an observable barrier as a requirement for function is incompatible with the ability of a protein to fold via sing le-exponential kinetics. [References: 64]
机译：由于β-折叠形成与淀粉样疾病的发生和传播相关，因此寻求模型系统以进一步了解这一过程。 WW域已被提议为一种这样的模型系统。尽管已显示来自人Yes关联蛋白（YAP）和Pin的WW结构域的折叠遵循单指数动力学，但已显示来自甲酰胺结合蛋白（FBP）28的WW结构域的折叠是通过两相进行的动力学。从原子级分子动力学模拟对自由能态势的分析中，在FBP WW域中观察到的双相折叠动力学可以追溯到该M域在其疏水核中采用两种略有不同的堆积形式的能力。这种构象变化沿肽主链传播，并影响其他WW域中色氨酸残基的位置，从而在结合中起关键作用。 Pin和YAP的WW域各自不支持一种以上的堆积，导致单相折叠动力学。 FBP WW结构域承担两种不同类型堆积的能力反过来可以解释该WW结构域结合两类配体的能力，这是其他WW结构域所不具有的特性。这些发现导致了这样的假设，即对于功能需求而言，由可观察的屏障分隔的构象的不稳定性与蛋白质通过单指数动力学折叠的能力不相容。 [参考：64]

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