Structure-function-folding relationship in a WW domain
Structure-function-folding relationship in a WW domain
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DOI：
10.1073/pnas.0600511103
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发表时间：
2006-07-11
影响因子：
11.1
通讯作者：
Kelly, Jeffery W.
中科院分区：
文献类型：
--
作者：
Jaeger, Marcus;Zhang, Yan;Kelly, Jeffery W.
蛋白质折叠障碍是由多种因素共同作用的结果，包括来自非原生相互作用的不可避免的能量挫折，氨基酸序列的自然变异和功能选择，以及/或聚集的选择压力。人类Pin1 WW结构域折叠的限速步骤是环路1子结构的形成。这个六残基环的天然构象定位侧链，这对于通过结合富含pro的序列介导蛋白质之间的相互作用是重要的。用更短的序列取代野生型环1初级结构，这些序列具有高倾向于折叠成i型' β -turn构象或统计上首选的i型G1凸起构象，加速了WW结构域折叠几乎一个数量级，并增加了热力学稳定性。然而，优化折叠能量学的环工程有明显的缺点：根据配体结合研究，它有效地消除了WW结构域功能。环1对配体结合的能量贡献似乎是以牺牲快速折叠和额外的蛋白质稳定性为代价的。因此，野生型人类Pin1 WW结构域所表现出的双态屏障主要是由于功能需求，而不是由于最有效的环形成过程所固有的物理限制。
Protein folding barriers result from a combination of factors including unavoidable energetic frustration from nonnative interactions, natural variation and selection of the amino acid sequence for function, and/or selection pressure against aggregation. The rate-limiting step for human Pin1 WW domain folding is the formation of the loop 1 substructure. The native conformation of this six-residue loop positions side chains that are important for mediating protein-protein interactions through the binding of Pro-rich sequences. Replacement of the wild-type loop 1 primary structure by shorter sequences with a high propensity to fold into a type-I'beta-turn conformation or the statistically preferred type-I G1 bulge conformation accelerates WW domain folding by almost an order of magnitude and increases thermodynamic stability. However, loop engineering to optimize folding energetics has a significant downside: it effectively eliminates WW domain function according to ligand-binding studies. The energetic contribution of loop 1 to ligand binding appears to have evolved at the expense of fast folding and additional protein stability. Thus, the two-state barrier exhibited by the wild-type human Pin1 WW domain principally results from functional requirements, rather than from physical constraints inherent to even the most efficient loop formation process.