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首页> 外文期刊>Journal of Molecular Biology >Circularization changes the folding transition state of the src SH3 domain
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Circularization changes the folding transition state of the src SH3 domain

机译：环化会更改src SH3域的折叠过渡状态

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摘要

Native state topology has been implicated as a major determinant of protein-folding mechanisms. Here, we test experimentally the robustness of the src SH3-domain folding transition state to changes in topology by covalently constraining regions of the protein with disulfide crosslinks and then performing kinetic analysis on point mutations in the context of these modified proteins. Circularization (crosslinking the N and C termini) of the src SH3 domain makes the protein topologically symmetric and causes delocalization of structure in the transition state ensemble suggesting a change in the folding mechanism. In contrast, crosslinking a single structural element (the distal beta -hairpin) which is an essential part of the transition state, results in a protein that folds 30 times faster, but does not change the distribution of structure in the transition state. As the transition states of distantly related SH3 domains were previously found to be very similar, we conclude that the free energy landscape of this protein family contains deep features which are relatively insensitive to sequence variations but can be altered by changes in topology.
机译：原始状态拓扑已被认为是蛋白质折叠机制的主要决定因素。在这里，我们通过共价约束二硫键交联的蛋白质区域，然后在这些修饰的蛋白质的背景下对点突变进行动力学分析，实验性地测试了src SH3结构域折叠过渡态对拓扑变化的鲁棒性。 src SH3结构域的环化作用（使N和C末端交联）使蛋白质在拓扑上对称，并导致过渡状态集合中结构的离域，提示折叠机制发生了变化。相反，交联作为过渡状态必不可少的单个结构元件（远侧β-发夹）会导致蛋白质折叠速度加快30倍，但不会改变过渡状态下结构的分布。由于以前发现相距遥远的SH3结构域的过渡态非常相似，因此我们得出结论，该蛋白家族的自由能格局包含对序列变异相对不敏感的深层特征，但可以通过拓扑结构的改变来改变。

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