A cyclic lipopeptide surfactin is a species-selective Hsp90 inhibitor that suppresses cyanobacterial growth
A cyclic lipopeptide surfactin is a species-selective Hsp90 inhibitor that suppresses cyanobacterial growth
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DOI：
10.1093/jb/mvab037
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发表时间：
2021-03-26
影响因子：
2.7
通讯作者：
Miyata, Yoshihiko
中科院分区：
文献类型：
--
作者：
Nakamoto, Hitoshi;Yokoyama, Yuhei;Miyata, Yoshihiko
热休克蛋白90（Hsp90）是真核细胞所必需的，而细菌同源物在应激和发病机制中发挥作用。鉴定物种特异性Hsp90抑制剂具有挑战性，因为Hsp90在进化上是保守的。我们发现，一种环状脂肽表面活性素抑制蓝细菌细长聚球藻（S.elongatus）PCC 7942的Hsp90的ATP酶活性，但不抑制大肠杆菌（E. coli）、酵母和人Hsp90。分子对接模拟结果表明，surfactin可与蓝藻Hsp90的N端二聚化界面结合，并与ATP和ADP结合，为研究其物种选择性抑制作用提供了分子基础。这些数据表明，表面活性素抑制细长聚球藻Hsp90在ATP水解中的限速构象变化。表面活性剂也抑制了蓝藻热休克蛋白90与模型基板的相互作用，并抑制了细长藻生长热应力下，但不是大肠杆菌。表面活性素对哺乳动物细胞没有显示出显著的细胞毒性。这些结果表明，表面活性素抑制Hsp90的细胞功能，特别是在蓝藻。本研究表明，环肽具有很强的特异性，可与高度保守的蛋白质家族的特定同源物相互作用。
Heat shock protein 90 (Hsp90) is essential for eukaryotic cells, whereas bacterial homologs play a role under stresses and in pathogenesis. Identifying species-specific Hsp90 inhibitors is challenging because Hsp90 is evolutionarily conserved. We found that a cyclic lipopeptide surfactin inhibits the ATPase activity of Hsp90 from the cyanobacterium Synechococcus elongatus (S.elongatus) PCC 7942 but does not inhibit Escherichia coli (E. coli), yeast and human Hsp90s. Molecular docking simulations indicated that surfactin could bind to the N-terminal dimerization interface of the cyanobacterial Hsp90 in the ATP- and ADP-bound states, which provided molecular insights into the species-selective inhibition. The data suggest that surfactin inhibits a rate-limiting conformational change of S.elongatus Hsp90 in the ATP hydrolysis. Surfactin also inhibited the interaction of the cyanobacterial Hsp90 with a model substrate, and suppressed S.elongatus growth under heat stress, but not that of E.coli. Surfactin did not show significant cellular toxicity towards mammalian cells. These results indicate that surfactin inhibits the cellular function of Hsp90 specifically in the cyanobacterium. The present study shows that a cyclic peptide has a great specificity to interact with a specific homolog of a highly conserved protein family.