Allosteric fine-tuning of the conformational equilibrium poises the chaperone BiP for post-translational regulation.
Allosteric fine-tuning of the conformational equilibrium poises the chaperone BiP for post-translational regulation.
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DOI：
10.7554/elife.29430
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发表时间：
2017-10-24
期刊：
影响因子：
7.7
通讯作者：
Zhuravleva A
中科院分区：
文献类型：
--
作者：
Wieteska L;Shahidi S;Zhuravleva A
BiP是内质网中唯一的Hsp70分子伴侣，与其他Hsp70类似，其活性依赖于其核苷酸结合域（NBD）和底物结合域（SBD）的核苷酸和底物可控对接和去对接。然而，很少有人知道的具体功能的BiP构象景观，调整BiP其独特的任务和ER环境。我们提出了甲基NMR分析的BiP分子伴侣循环，揭示了令人惊讶的构象异质性的ATP结合的BiP，区分BiP从其细菌同系物DnaK。这种不寻常的平衡使得能够通过SBD变构“热点”处的细微局部扰动来逐渐调节BiP分子伴侣循环及其分子伴侣活性。特别地，通过其SBD的AMP化的BiP失活不干扰Hsp70结构域间变构并且保留BiP结构。相反，它依赖于在ADP和ATP存在下BiP构象集合的重新分布和结构域对接构象的稳定。
BiP is the only Hsp70 chaperone in the endoplasmic reticulum (ER) and similar to other Hsp70s, its activity relies on nucleotide- and substrate-controllable docking and undocking of its nucleotide-binding domain (NBD) and substrate-binding domain (SBD). However, little is known of specific features of the BiP conformational landscape that tune BiP to its unique tasks and the ER environment. We present methyl NMR analysis of the BiP chaperone cycle that reveals surprising conformational heterogeneity of ATP-bound BiP that distinguishes BiP from its bacterial homologue DnaK. This unusual poise enables gradual post-translational regulation of the BiP chaperone cycle and its chaperone activity by subtle local perturbations at SBD allosteric ‘hotspots’. In particular, BiP inactivation by AMPylation of its SBD does not disturb Hsp70 inter-domain allostery and preserves BiP structure. Instead it relies on a redistribution of the BiP conformational ensemble and stabilization the domain-docked conformation in presence of ADP and ATP.