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首页> 外文期刊>Biochemistry >A Conserved Interdomain Interaction Is a Determinant of Folding Cooperativity in the GST Fold
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A Conserved Interdomain Interaction Is a Determinant of Folding Cooperativity in the GST Fold

机译：保守的域间交互作用是GST折叠中折叠合作性的决定因素。

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摘要

The canonical glutathione transferase (GST) fold found in many monomeric and dimeric proteins consists of two domains that differ in structure and conformational dynamics. However, no evidence exists that the two domains unfold/fold independently at equilibrium, indicating the significance of interdomain interactions in governing cooperativity between domains. Bioinformatics analyses indicate the interdomain interface of the GST fold is large, predominantly hydrophobic with a high packing density explaining cooperative interdomain behavior. Structural alignments reveal a topologically conserved lock-and-key interaction across the domain interface in which a bulky hydrophobic residue (“key”) protrudes from the surface of the N-domain and inserts into a pocket (“lock”) in the C-domain. To better understand the molecular basis for the contribution of interdomain interactions toward cooperativity within the GST fold in the absence of any influence from quaternary interactions, studies were done with two monomeric GST proteins: Escherichia coli Grx2 (EcGrx2) and human CLIC1 (hCLIC1). Replacing the methionine “key” residue with alanine is structurally nondisruptive, whereas it significantly diminishes the folding cooperativity of both proteins. The loss in cooperativity between domains in the mutants is reflected by a change in the equilibrium folding mechanism from a wild-type two-state process to a three-state process, populating a stable folding intermediate.
机译：在许多单体和二聚体蛋白质中发现的标准谷胱甘肽转移酶（GST）折叠由结构和构象动力学不同的两个域组成。但是，没有证据表明两个结构域在平衡状态下独立展开/折叠，这表明域间相互作用在控制域之间的协作性方面具有重要意义。生物信息学分析表明，GST折叠的域间界面很大，主要是疏水性的，具有很高的堆积密度，这说明了协同域间行为。结构比对揭示了跨域接口的拓扑保守的锁键相互作用，其中大块疏水残基（“键”）从N域表面突出，并插入C-的口袋中（“锁”）域。为了更好地理解在不受到四元相互作用的任何影响的情况下，域间相互作用对GST折叠内协同作用的贡献的分子基础，我们对两种单体GST蛋白进行了研究：大肠杆菌Grx2（EcGrx2）和人CLIC1（hCLIC1）。用丙氨酸取代蛋氨酸的“关键”残基在结构上无破坏性，而它却大大降低了这两种蛋白质的折叠协同性。突变体中结构域之间协作性的丧失反映在平衡折叠机制从野生型两态过程到三态过程的变化中，该过程填充了稳定的折叠中间体。

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