Extracting function from a β-trefoil folding motif
Extracting function from a β-trefoil folding motif
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DOI：
10.1073/pnas.0801343105
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发表时间：
2008-07-29
影响因子：
11.1
通讯作者：
Onuchic, Jose N.
中科院分区：
文献类型：
--
作者：
Gosavi, Shachi;Whitford, Paul C.;Onuchic, Jose N.
尽管具有非常相似的三维结构和稳定性，IL-1 β促进信号传导，而IL-1 Ra抑制它。它们的能量景观是相似的，并共同进化，以促进与IL-1受体的竞争性结合。然而，我们发现IL-1 Ra比IL-1 β折叠得更快。蛋白质的结构比对显示主要在两个环中的差异，IL-1 β的β-凸起和IL-1 Ra中与残基K145相互作用并连接β-链11和12的环。生物测定表明，插入IL-1 β的β凸起赋予IL-1 Ra的K145 D突变体部分信号传导能力。基于比对、突变分析和我们的计算折叠结果，我们假设功能区域不是β-三叶基序的中心，并导致缓慢折叠。IL-1 β的β凸起促进活性，并被IL-1 Ra β转角取代，导致杂交蛋白比IL-1 β折叠得更快。将有助于抑制的β 11-β 12连接环插入IL-1 β或杂合蛋白中会减缓折叠。因此，可以通过结构差异从折叠陷阱中推断出辅助功能（通过活性或抑制）的区域。将功能特性映射到结构基因组学工作中确定的众多折叠上是一个非常感兴趣的领域。我们的研究提供了一个系统的方法来映射折叠家庭的功能基因组学。
Despite having remarkably similar three-dimensional structures and stabilities, IL-1 beta promotes signaling, whereas IL-1Ra inhibits it. Their energy landscapes are similar and have coevolved to facilitate competitive binding to the IL-1 receptor. Nevertheless, we find that IL-1Ra folds faster than IL-1 beta. A structural alignment of the proteins shows differences mainly in two loops, a beta-bulge of IL-1 beta and a loop in IL-1 Ra that interacts with residue K145 and connects beta-strands 11 and 12. Bioassays indicate that inserting the beta-bulge from IL-1 beta confers partial signaling capability onto a K145D mutant of IL-1Ra. Based on the alignment, mutational assays and our computational folding results, we hypothesize that functional regions are not central to the beta-trefoil motif and cause slow folding. The IL-1 beta beta-bulge facilitates activity and replacing it by the IL-1Ra beta-turn results in a hybrid protein that folds fasterthan IL-1 beta. Inserting the beta 11-beta 12 connecting-loop, which aids inhibition, into either IL-1 beta or the hybrid protein slows folding. Thus, regions that aid function (either through activity or inhibition) can be inferred from folding traps via structural differences. Mapping functional properties onto the numerous folds determined in structural genomics efforts is an area of intense interest. Our studies provide a systematic approach to mapping the functional genomics of a fold family.