Rapid evolution in conformational space: A study of loop regions in a ubiquitous GTP binding domain
Rapid evolution in conformational space: A study of loop regions in a ubiquitous GTP binding domain
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DOI：
10.1110/ps.03299804
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发表时间：
2004-03-01
期刊：
影响因子：
8
通讯作者：
Roger, AJ
中科院分区：
文献类型：
--
作者：
Blouin, C;Butt, D;Roger, AJ
蛋白质的快速进化的亚集通常在多个序列比对中很明显，作为定义不明确的包含间隙的区域。我们研究了在28个含有GTP结合域的蛋白质结构中观察到的这些区域的3D背景，这些结构域被认为与转化因子p21-RAS同源。这个数据集的系统发育深度是这样的，它可以观察到在真核细胞历史早期分歧的共同蛋白质核心的谱系。这些同源蛋白之间的序列可变性与表面环的结构可变性直接相关。我们证明这些区域是自给自足的，因此大部分不受结构域保守核心施加的进化限制。这些环内相互作用具有创建茎状结构的特性。有趣的是，这些茎状结构可以在不同大小的环中观察到，甚至可以观察到小蛋白结构域的大小。我们提出了一个模型，在该模型下，在这些环中观察到的蛋白质拓扑的多样性可以是以近中性方式对序列和构象空间进行随机采样的产物，而结构域核心的功能特征的接近允许新的有益特征被固定。我们的比较观察，这里仅限于包含RAS样GTP结合域的蛋白质，表明类似于环的“萌芽”的随机插入/缺失过程是结构创新的一种可能机制。这样的框架可以被实验性地利用来研究日益复杂的模型插件的折叠。
The rapidly evolving subsets of a protein are often evident in multiple sequence alignments as poorly defined, gap-containing regions. We investigated the 3D context of these regions observed in 28 protein structures containing a GTP-binding domain assumed to be homologous to the transforming factor p21-RAS. The phylogenetic depth of this data set is such that it is possible to observe lineages sharing a common protein core that diverged early in the eukaryotic cell history. The sequence variability among these homolog proteins is directly linked to the structural variability of surface loops. We demonstrate that these regions are self-contained and thus mostly free of the evolutionary constraints imposed by the conserved core of the domain. These intraloop interactions have the property to create stem-like structures. Interestingly, these stem-like structures can be observed in loops of varying size, up to the size of small protein domains. We propose a model under which the diversity of protein topologies observed in these loops can be the product of a stochastic sampling of sequence and conformational space in a near-neutral fashion, while the proximity of the functional features of the domain core allows novel beneficial traits to be fixed. Our comparative observations, limited here to the proteins containing the RAS-like GTP-binding domain, suggest that a stochastic process of insertion/deletion analogous to "budding" of loops is a likely mechanism of structural innovation. Such a framework could be experimentally exploited to investigate the folding of increasingly complex model inserts.