期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 60, 期 3, 页码 1614-1631出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.9b01045
关键词
-
类别
资金
- Kay Family Foundation Data Analytics Grant [A20-0032]
Structural and biochemical studies of Hsp70 chaperones have provided a molecular view of the chaperone biochemical cycle by revealing a complex interplay between allosteric conformational states that controls the feedback loop between stimulation of the adenosinetriphosphatase (ATPase) activity and the substrate release. Allosteric regulation in the Hsp70 chaperones and efficient substrate targeting are mediated by J-domain cochaperones through a dynamic interaction network controlled by the regulatory hotspots. In the current work, we have simulated conformational landscapes and residue interaction networks in the open, closed, and cochaperone-bound DnaK structures. The results of this work have shown that J-domain can selectively enhance direction-specific signal propagation from the substrate-binding domain to the catalytic center and promote the structural environment required for ATP hydrolysis. By employing different network-based approaches, we examined the role and contribution of post-translational modification sites in allosteric regulation of human Hsp70. The central finding of this analysis indicated that conserved phosphorylation sites localized preferentially in the nucleotide-binding domain regions are often aligned with the allosteric control points and serve as effector centers in Hsp70. We have found that cooperation of post-translational modifications sites is based on the governing role of phosphorylation sites in dictating regulatory switching functions, whereas the bulk of acetylation sites can be involved in sensing the long-range signals and executing allosteric changes during the ATPase cycle. The results of this study highlight the important role of phosphorylation sites in exerting control over allosteric changes in Hsp70. The network-centric framework for the analysis of conformational dynamics and chaperone landscapes can explain a range of structural and functional experiments, providing a robust dynamic model of Hsp70 regulation by cochaperones and sites of post-translational modifications.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据