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首页> 外文期刊>Journal of Molecular Biology >Rough energy landscapes in protein folding: Dimeric E-coliTrp repressor folds through three parallel channels
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Rough energy landscapes in protein folding: Dimeric E-coliTrp repressor folds through three parallel channels

机译：蛋白质折叠中的粗糙能量景观：二聚E-coliTrp阻遏物通过三个平行通道折叠

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摘要

The folding mechanism of the dimeric Escherichia coli Trp repressor (TR) is a kinetically complex process that involves three distinguishable stages of development. Following the formation of a partially folded, monomeric ensemble of species, within 5 ms, folding to the native dimer is controlled by three kinetic phases. The rate-limiting step in each phase is either a non-proline isomerization. reaction or a dimerization reaction, depending on the final denaturant concentration. Two approaches have been employed to test the previously proposed folding mechanism of TR through three parallel channels: (1) unfolding double-jump experiments demonstrate that all three folding channels lead directly to native dimer; and (2) the differential stabilization of the transition state for the final step in folding and the native dimer, by the addition of salt, shows that all three channels involve isomerization of a dimeric species. A refined model for the folding of Trp repressor is presented, in which all three channels involve a rapid dimerization reaction between partially folded monomers followed by the isomerization of the dimeric intermediates to yield native dimer. The ensemble of partially folded monomers can be captured at equilibrium by low pH; one-dimensional proton NMR spectra at pH 2.5 demonstrate that monomers exist in two distinct, slowly interconverting conformations. These data provide a potential structural explanation for the three-channel folding mechanism of TR: random association of two different monomeric forms, which are distinguished by alternative packing modes of the core dimerization domain and the DNA-binding, helix-turn-helix, domain. One, perhaps both, of these packing modes contains non-native contacts.
机译：二聚体大肠杆菌Trp阻遏物（TR）的折叠机制是一个动力学复杂的过程，涉及三个不同的发展阶段。在物种形成部分折叠的单体集合之后，在5毫秒内，通过三个动力学阶段控制折叠成天然二聚体。每个阶段中的限速步骤是非脯氨酸异构化。反应或二聚反应，取决于最终变性剂的浓度。已采用两种方法通过三个平行通道测试TR的折叠机制：（1）展开双跳实验表明，所有三个折叠通道均直接导致天然二聚体; （2）通过添加盐，折叠的最后一步和天然二聚体的过渡态的差异稳定，表明所有三个通道都涉及二聚体的异构化。提出了一种用于Trp阻遏物折叠的改进模型，其中所有三个通道都涉及部分折叠的单体之间的快速二聚反应，然后是二聚中间体的异构化以产生天然二聚体。低pH可在平衡状态下捕获部分折叠的单体。 pH为2.5时的一维质子NMR光谱表明，单体以两种不同的缓慢互变构象存在。这些数据为TR的三通道折叠机制提供了潜在的结构解释：两种不同单体形式的随机缔合，其区别在于核心二聚化结构域和DNA结合结构（螺旋-转-螺旋）结构域的替代堆积模式。这些打包方式中的一种（或两种）都包含非本地联系人。

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