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PNAS:浙江大学张纬萍课题组等发表泛素研究成果

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摘要 : 近日,国际著名学术期刊《美国科学院院刊》在线发表了浙江大学医学院张纬萍副教授带领的研究团队和中国科学院武汉物理与数学研究所唐淳研究员课题组合作的题为“Ubiquitin S65 phosphorylation engenders a pH-sensitive conformational switch”研究论文。

近日,国际著名学术期刊《美国科学院院刊》在线发表了浙江大学医学院张纬萍副教授带领的研究团队和中国科学院武汉物理与数学研究所唐淳研究员课题组合作的题为“Ubiquitin S65 phosphorylation engenders a pH-sensitive conformational switch”研究论文。研究发现泛素单体的S65被磷酸化后,呈现四种能够相互变化的构象,研究解析了每种构象的结构,发现这四种构象的组成比例受pH值调节,变化最灵敏的pH值范围在6.0-8.0之间;而且,泛素单体的构象变化还影响到泛素链的四级结构,导致泛素能够与不同的靶蛋白结合,执行不同的功能。

泛素在细胞内广泛存在,泛素通过与靶蛋白特异性的相互作用发挥功能。目前已知能与泛素结合的靶蛋白已达上千种,这些靶蛋白的结构和功能各异,泛素如何特异性识别如此众多的靶标,这一问题尚未完全阐明。2014年,发表于《Nature》杂志的一篇报道首次指出泛素S65能够被磷酸化,进而影响泛素的功能,并指出磷酸化可以使泛素的功能变得“多元化”。此次他们在《PNAS》上的报道,为阐释泛素功能“多元化”现象提供了有力的证据,并提出了新的泛素功能调节因素。在细胞中,不同亚细胞部位有不同的pH值,且细胞在不同的生理和病理状态下,这些pH值会发生变化。因此,此次发现pH值影响磷酸化泛素的结构和功能,可为了解泛素信号系统、揭示细胞功能变化带来新思路和新方向,对生物学研究具有深远的影响。

PNAS:浙江大学张纬萍课题组等发表泛素研究成果
原文链接:

Ubiquitin S65 phosphorylation engenders a pH-sensitive conformational switch

原文摘要:

Ubiquitin (Ub) is an important signaling protein. Recent studies have shown that Ub can be enzymatically phosphorylated at S65, and that the resulting pUb exhibits two conformational states—a relaxed state and a retracted state. However, crystallization efforts have yielded only the structure for the relaxed state, which was found similar to that of unmodified Ub. Here we present the solution structures of pUb in both states obtained through refinement against state-specific NMR restraints. We show that the retracted state differs from the relaxed state by the retraction of the last β-strand and by the extension of the second α-helix. Further, we show that at 7.2, the pKa value for the phosphoryl group in the relaxed state is higher by 1.4 units than that in the retracted state. Consequently, pUb exists in equilibrium between protonated and deprotonated forms and between retracted and relaxed states, with protonated/relaxed species enriched at slightly acidic pH and deprotonated/retracted species enriched at slightly basic pH. The heteroGENEity of pUb explains the inability of phosphomimetic mutants to fully mimic pUb. The pH-sensitive conformational switch is likely preserved for polyubiquitin, as single-molecule FRET data indicate that pH change leads to quaternary rearrangement of a phosphorylated K63-linked diubiquitin. Because cellular pH varies among compartments and changes upon pathophysiological insults, our finding suggests that pH and Ub phosphorylation confer additional target specificities and enable an additional layer of modulation for Ub signals.

doi:10.1073/pnas.1705718114

作者:张纬萍 点击:

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