生物
突变体
热休克蛋白90
泛素连接酶
热休克蛋白70
伴侣(临床)
DNA
细胞生物学
DNA结合域
平方毫米
构象变化
绑定域
野生型
生物化学
生物物理学
泛素
热休克蛋白
结合位点
转录因子
细胞凋亡
病理
基因
医学
作者
Marta Boysen,Roman Kityk,Matthias P. Mayer
出处
期刊:Molecular Cell
[Elsevier]
日期:2019-05-01
卷期号:74 (4): 831-843.e4
被引量:83
标识
DOI:10.1016/j.molcel.2019.03.032
摘要
The activity of the tumor suppressor p53 has to be timed and balanced closely to prevent untimely induction of cell death. The stability of p53 depends on the ubiquitin ligase Mdm2 but also on Hsp70 and Hsp90 chaperones that interact with its DNA binding domain (DBD). Using hydrogen exchange mass spectrometry and biochemical methods, we analyzed conformational states of wild-type p53-DBD at physiological temperatures and conformational perturbations in three frequent p53 cancer mutants. We demonstrate that the Hsp70/Hdj1 system shifts the conformational equilibrium of p53 toward a flexible, more mutant-like, DNA binding inactive state by binding to the DNA binding loop. The analyzed cancer mutants are likewise destabilized by interaction with the Hsp70/Hdj1 system. In contrast, Hsp90 protects the DBD of p53 wild-type and mutant proteins from unfolding. We propose that the Hsp70 and Hsp90 chaperone systems assume complementary functions to optimally balance conformational plasticity with conformational stability.
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