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首页> 外文期刊>Journal of Molecular Biology >Kinetic intermediates of beta(2)-microglobulin fibril elongation probed by pulse-labeling H/D exchange combined with NMR analysis.
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Kinetic intermediates of beta(2)-microglobulin fibril elongation probed by pulse-labeling H/D exchange combined with NMR analysis.

机译：通过脉冲标记H / D交换结合NMR分析探测的β（2）-微球蛋白原纤维伸长的动力学中间体。

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摘要

Amyloid fibril elongation in denatured proteins involves cycles of coupled binding and misfolding. To gain insights into possible kinetic intermediates, we performed hydrogen/deuterium exchange of amide protons during fibril elongation with beta(2)-microglobulin (beta(2)-m) at pD=2.5, under which conditions beta(2)-m is acid denatured. To study the conformational change in monomeric beta(2)-m monitored by NMR spectroscopy, we used (15)N-labeled monomers and nonlabeled seeds. Pulse-labeling hydrogen/deuterium exchange with a quenched-flow apparatus indicated that the rate-limiting intermediate at pD=2.5 is not protected from the exchange, even disrupting a hydrophobic cluster present in the acid-denatured beta(2)-m. Significant protection was acquired upon transition to the fibrils. In view of the suggestion that the rate-limiting intermediates are bound to the lateral surface of seed fibrils, weak interactions with a largely unfolded conformation might be useful for their dynamic sliding to the growing ends. The results support a new model of fibril elongation with intermediates bound to the lateral surface of seeds.
机译：变性蛋白质中淀粉样蛋白原纤维的延伸涉及结合结合和错误折叠的循环。为了深入了解可能的动力学中间体，我们在原纤维伸长过程中与β（2）-微球蛋白（β（2）-m）在pD = 2.5时进行了氢/氘交换酰胺质子，在这种情况下，β（2）-m为酸变性。要研究通过NMR光谱监测单体β（2）-m的构象变化，我们使用了（15）N标记的单体和未标记的种子。用淬灭流装置对氢/氘进行脉冲标记表明，pD = 2.5的限速中间体没有受到交换的保护，甚至破坏了酸性变性β（2）-m中的疏水簇。过渡到原纤维后获得了显着的保护。考虑到限速中间体被束缚在种子原纤维的侧表面上的建议，弱相互作用与很大程度上展开的构象可能对于它们向生长末端的动态滑动可能是有用的。结果支持了一种新的原纤维伸长模型，其中中间体与种子的侧面结合。

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