Department of Chemistry, Technische Universität München, Lichtenbergstr. 4, 85747, Garching, Germany.
Institut für Mikrobiologie der Bundeswehr, Neuherbergstr.11, 80937, München, Germany.
Nat Commun. 2020 Mar 5;11(1):1219. doi: 10.1038/s41467-020-15048-8.
Methylation of a conserved lysine in C-terminal domain of the molecular chaperone Hsp90 was shown previously to affect its in vivo function. However, the underlying mechanism remained elusive. Through a combined experimental and computational approach, this study shows that this site is very sensitive to sidechain modifications and crucial for Hsp90 activity in vitro and in vivo. Our results demonstrate that this particular lysine serves as a switch point for the regulation of Hsp90 functions by influencing its conformational cycle, ATPase activity, co-chaperone regulation, and client activation of yeast and human Hsp90. Incorporation of the methylated lysine via genetic code expansion specifically shows that upon modification, the conformational cycle of Hsp90 is altered. Molecular dynamics simulations including the methylated lysine suggest specific conformational changes that are propagated through Hsp90. Thus, methylation of the C-terminal lysine allows a precise allosteric tuning of Hsp90 activity via long distances.
先前的研究表明，分子伴侣 Hsp90 羧基末端结构域中一个保守赖氨酸的甲基化会影响其体内功能。但是，其潜在的机制仍然难以捉摸。通过综合实验和计算方法，本研究表明该位点对侧链修饰非常敏感，并且对 Hsp90 在体外和体内的活性至关重要。我们的结果表明，该特定赖氨酸作为开关点，通过影响其构象循环、ATP 酶活性、共伴侣调节以及酵母和人 Hsp90 的客户激活，来调节 Hsp90 功能。通过遗传密码扩展特异性地掺入甲基化赖氨酸表明，修饰后，Hsp90 的构象循环发生改变。包括甲基化赖氨酸在内的分子动力学模拟表明，构象变化会通过 Hsp90 传播。因此，羧基末端赖氨酸的甲基化允许通过远距离对 Hsp90 活性进行精确的变构调节。
