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首页> 外文期刊>Journal of Molecular Biology >Hydrogen/Deuterium Exchange Mass Spectrometric Analysis of Conformational Changes Accompanying the Assembly of the Yeast Prion Ure2p into Protein Fibrils
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Hydrogen/Deuterium Exchange Mass Spectrometric Analysis of Conformational Changes Accompanying the Assembly of the Yeast Prion Ure2p into Protein Fibrils

机译：氢/氘交换质谱分析伴随酵母Pri病毒Ure2p组装成蛋白质原纤维的构象变化

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摘要

The Ure2 protein from baker's yeast (Saccharomyces cerevisiae) has prion properties. In vitro, at neutral pH, soluble Ure2p forms long, twisted fibrils. Two models have been proposed to account for Ure2p polymerization. The first postulates that a segment of 70 amino acid residues in the flexible N-terminal domain from different Ure2p molecules forms a parallel superpleated β-structure running along the fibrils. The second hypothesizes that assembly of full-length Ure2p is driven by limited conformational rearrangements and non-native inter- and intramolecular interactions. The knowledge of the three-dimensional structure of the fibrillar form of Ure2p is critical for understanding the molecular events leading to the polymerization of soluble Ure2p into fibrils and hence for the design of inhibitors that might have therapeutic potential as yeast prions possessing domains rich in N and Q residues, similar to huntingtin. Solvent-accessibility studies using hydrogen/deuterium exchange monitored by mass spectrometry (HXMS) can provide insights into the structure of the fibrillar form of Ure2p and characterize at the molecular level the conformational rearrangements that occur upon assembly, in particular through the identification of protected regions and their localization in the overall structure of the protein. We have analyzed the changes in Ure2p structure associated with its assembly into fibrils using HXMS. The deuterium incorporation profile along the sequence allows the identification of the regions that exhibit the most important conformational change. Our data reveal that Ure2p undergoes minor structural changes upon assembly. While polypeptides [82-92] and [13-37] exhibit significant increased and decreased exposure to the solvent, respectively, no marked change was observed for the rest of the protein upon assembly. Our results afford new insights into the conformational rearrangements that lead to the assembly of Ure2p into fibrils and the propagation of the [URE3] element in yeast.
机译：面包酵母（Saccharomyces cerevisiae）中的Ure2蛋白具有病毒特性。在体外，在中性pH下，可溶性Ure2p会形成较长的扭曲原纤维。已经提出了两种模型来解释Ure2p聚合。第一个假设是，来自不同的Ure2p分子的柔性N端结构域中70个氨基酸残基的片段形成了沿着原纤维延伸的平行，重叠的β结构。第二个假设是全长Ure2p的组装受有限的构象重排以及非天然的分子间和分子内相互作用驱动。 Ure2p的原纤维形式的三维结构知识对于理解导致可溶性Ure2p聚合成原纤维的分子事件，因此对于设计可能具有治疗潜力的抑制剂inhibitor具有丰富的N结构的病毒抑制剂至关重要。和Q残基，类似于亨廷顿蛋白。使用质谱仪（HXMS）监测的氢/氘交换的溶剂可及性研究可以洞悉Ure2p的原纤维形式的结构，并在分子水平上表征组装时发生的构象重排，特别是通过识别保护区以及它们在蛋白质整体结构中的定位。我们已经使用HXMS分析了Ure2p结构与其组装成原纤维相关的变化。沿着序列的氘掺入曲线允许鉴定出表现出最重要的构象变化的区域。我们的数据表明，Ure2p在组装时会发生较小的结构变化。尽管多肽[82-92]和[13-37]分别显示出显着增加和减少的暴露于溶剂，但组装后其余蛋白质未观察到明显变化。我们的结果为构象重排提供了新的见解，这些构象重排​​导致Ure2p组装成原纤维以及[URE3]元素在酵母中的传播。

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