Coiled coils at the edge of configurational heterogeneity. Structural analyses of parallel and antiparallel homotetrameric coiled coils reveal configurational sensitivity to a single solvent-exposed amino acid substitution
Coiled coils at the edge of configurational heterogeneity. Structural analyses of parallel and antiparallel homotetrameric coiled coils reveal configurational sensitivity to a single solvent-exposed amino acid substitution
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DOI：
10.1021/bi060092q
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发表时间：
2006-04-11
期刊：
影响因子：
2.9
通讯作者：
Ghadiri, MR
中科院分区：
文献类型：
--
作者：
Yadav, MK;Leman, LJ;Ghadiri, MR
详细了解特定氨基酸序列可以产生一个以上折叠结构的机制，例如经历大构象变化或错误折叠的蛋白质，是蛋白质化学的长期目标。在这里，我们描述了不同的平行和反平行四聚体构型的单个卷曲螺旋肽的晶体结构，并进一步描述了几种相关肽序列的平行或反平行晶体结构，反平行四聚体组装体代表了表现出这种构型的GCN 4衍生肽的第一晶体结构。有趣的是，单个暴露于溶剂的残基的取代使得平行卷曲螺旋四聚体GCN 4-pLI能够填充反平行构型。这表明这两种构型在能量上足够接近，使得细微的序列变化具有重要的结构后果。我们提出了一个结构分析的小变化的螺旋寄存器和侧链构象，以适应这两种配置，并补充了这些结果，使用溶液的研究和分子动力学能量分析，使用副本交换方法。考虑到先前卷曲螺旋肽结构非特异性的例子。这里报道的发现不仅强调了卷曲螺旋基序采用多种构型的倾向，而且还引起了对所观察到的晶体结构可能不代表溶液中存在的唯一（或甚至主要）物质的相关风险的注意。
A detailed understanding of the mechanisms by which particular amino acid sequences can give rise to more than one folded Structure, such as for proteins that undergo large conformational changes or misfolding, is a long-standing objective of protein chemistry. Here, we describe the crystal structures of a single coiled-coil peptide in distinct parallel and antiparallel tetrameric configurations and further describe the parallel or antiparallel crystal Structures of several related peptide sequences, the antiparallel tetrameric assemblies represent the first crystal structures of GCN4-derived peptides exhibiting such a configuration. Intriguingly, substitution of a single solvent-exposed residue enabled the parallel coiled-coil tetramer GCN4-pLI to populate the antiparallel configuration. suggesting that the two configurations are close enough in energy for subtle sequence changes to have important structural consequences. We present a structural analysis of the small changes to the helix register and side-chain conformations that accommodate the two configurations and have Supplemented these results using solution studies and a molecular dynamics energetic analysis using a replica exchange methodology. Considering the previous examples of structural nonspecificity in coiled-coil peptides. the findings reported here not only emphasize the predisposition of the coiled-coil motif to adopt multiple configurations but also call attention to the associated risk that observed crytstal structures may not represent the only (or even the major) species present in solution.