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Molecular insights into mechanisms of GPCR hijacking by Staphylococcus aureus [Biochemistry]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2021-10-19 , DOI: 10.1073/pnas.2108856118
Claire M Grison 1 , Paul Lambey 1 , Sylvain Jeannot 1 , Elise Del Nero 1 , Simon Fontanel 1 , Fanny Peysson 1 , Joyce Heuninck 1 , Rémy Sounier 1 , Thierry Durroux 1 , Cédric Leyrat 1 , Sébastien Granier 2 , Cherine Bechara 2, 3
Affiliation  

Atypical chemokine receptor 1 (ACKR1) is a G protein–coupled receptor (GPCR) targeted by Staphylococcus aureus bicomponent pore-forming leukotoxins to promote bacterial growth and immune evasion. Here, we have developed an integrative molecular pharmacology and structural biology approach in order to characterize the effect of leukotoxins HlgA and HlgB on ACKR1 structure and function. Interestingly, using cell-based assays and native mass spectrometry, we found that both components HlgA and HlgB compete with endogenous chemokines through a direct binding with the extracellular domain of ACKR1. Unexpectedly, hydrogen/deuterium exchange mass spectrometry analysis revealed that toxin binding allosterically modulates the intracellular G protein–binding domain of the receptor, resulting in dissociation and/or changes in the architecture of ACKR1−Gαi1 protein complexes observed in living cells. Altogether, our study brings important molecular insights into the initial steps of leukotoxins targeting a host GPCR.



中文翻译:

金黄色葡萄球菌劫持 GPCR 机制的分子见解 [生物化学]

非典型趋化因子受体 1 (ACKR1) 是金黄色葡萄球菌靶向的 G 蛋白偶联受体 (GPCR)双组分成孔白细胞毒素促进细菌生长和免疫逃避。在这里,我们开发了一种综合分子药理学和结构生物学方法,以表征白细胞毒素 HlgA 和 HlgB 对 ACKR1 结构和功能的影响。有趣的是,使用基于细胞的分析和天然质谱,我们发现 HlgA 和 HlgB 两种成分都通过与 ACKR1 的细胞外结构域直接结合而与内源性趋化因子竞争。出乎意料的是,氢/氘交换质谱分析显示,毒素结合变构调节受体的细胞内 G 蛋白结合结构域,导致在活细胞中观察到的 ACKR1-Gαi1 蛋白复合物的解离和/或结构发生变化。共,

更新日期:2021-10-19
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