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Conformational maps of human 20S proteasomes reveal PA28- and immuno-dependent inter-ring crosstalks
Nature Communications ( IF 14.7 ) Pub Date : 2020-12-01 , DOI: 10.1038/s41467-020-19934-z
Jean Lesne 1, 2 , Marie Locard-Paulet 1, 3 , Julien Parra 1 , Dušan Zivković 1 , Thomas Menneteau 1, 4 , Marie-Pierre Bousquet 1 , Odile Burlet-Schiltz 1 , Julien Marcoux 1
Affiliation  

Hydrogen-Deuterium eXchange coupled to Mass Spectrometry (HDX-MS) is now common practice in structural biology. However, it is most of the time applied to rather small oligomeric complexes. Here, we report on the use of HDX-MS to investigate conformational differences between the human standard 20S (std20S) and immuno 20S (i20s) proteasomes alone or in complex with PA28αβ or PA28γ activators. Their solvent accessibility is analyzed through a dedicated bioinformatic pipeline including stringent statistical analysis and 3D visualization. These data confirm the existence of allosteric differences between the std20S and i20S at the surface of the α-ring triggered from inside the catalytic β-ring. Additionally, binding of the PA28 regulators to the 20S proteasomes modify solvent accessibility due to conformational changes of the β-rings. This work is not only a proof-of-concept that HDX-MS can be used to get structural insights on large multi-protein complexes in solution, it also demonstrates that the binding of the std20S or i20S subtype to any of its PA28 activator triggers allosteric changes that are specific to this 20S/PA28 pair.



中文翻译:


人类 20S 蛋白酶体的构象图揭示了 PA28 和免疫依赖性环间串扰



氢-氘交换与质谱 (HDX-MS) 结合现在是结构生物学的常见做法。然而,它大多数时候应用于相当小的寡聚复合物。在此,我们报告使用 HDX-MS 来研究人类标准 20S (std20S) 和免疫 20S (i20s) 蛋白酶体单独或与 PA28αβ 或 PA28γ 激活剂复合物之间的构象差异。它们的溶剂可及性通过专用的生物信息学管道进行分析,包括严格的统计分析和 3D 可视化。这些数据证实了 α 环表面的 std20S 和 i20S 之间存在由催化 β 环内部触发的变构差异。此外,由于 β 环的构象变化,PA28 调节剂与 20S 蛋白酶体的结合改变了溶剂可及性。这项工作不仅证明了 HDX-MS 可用于获得溶液中大型多蛋白复合物的结构见解,还证明了 std20S 或 i20S 亚型与其任何 PA28 激活剂的结合会触发这对 20S/PA28 特有的变构变化。

更新日期:2020-12-01
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