Perturbation-Response Scanning Reveals Key Residues for Allosteric Control in Hsp70

Journal of Chemical Information and Modeling
David PenklerÖzlem Tastan Bishop

Abstract

Hsp70 molecular chaperones play an important role in maintaining cellular homeostasis, and are implicated in a wide array of cellular processes, including protein recovery from aggregates, cross-membrane protein translocation, and protein biogenesis. Hsp70 consists of two domains, a nucleotide binding domain (NBD) and a substrate binding domain (SBD), each of which communicates via an allosteric mechanism such that the protein interconverts between two functional states, an ATP-bound open conformation and an ADP-bound closed conformation. The exact mechanism for interstate conversion is not as yet fully understood. However, the ligand-bound states of the NBD and SBD as well as interactions with cochaperones such as DnaJ and nucleotide exchange factor are thought to play crucial regulatory roles. In this study, we apply the perturbation-response scanning (PRS) method in combination with molecular dynamics simulations as a computational tool for the identification of allosteric hot residues in the large multidomain Hsp70 protein. We find evidence in support of the hypothesis that substrate binding triggers ATP hydrolysis and that the ADP-substrate complex favors interstate conversion to the closed state. Furthermore, our data are...Continue Reading

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Citations

Jun 3, 2017·Bioinformatics·David K BrownÖzlem Tastan Bishop
Oct 3, 2017·Metallomics : Integrated Biometal Science·H AbdizadehB Dedeoglu
Sep 13, 2018·Expert Opinion on Drug Discovery·Fisayo OlotuMahmoud Soliman
Jan 10, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Arnold Amusengeri, Özlem Tastan Bishop
Jul 30, 2017·The Journal of Biological Chemistry·Charles A EnglishLila M Gierasch
Feb 6, 2020·International Journal of Molecular Sciences·Olivier Sheik AmamuddyOzlem Tastan Bishop
Feb 23, 2020·Annual Review of Biophysics·Paul CampitelliS Banu Ozkan
Sep 20, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Aimen AljoundiMahmoud E S Soliman
Nov 14, 2019·International Journal of Molecular Sciences·Arnold AmusengeriÖzlem Tastan Bishop
Apr 14, 2020·Computational and Structural Biotechnology Journal·Zhongjie LiangGuang Hu
Mar 7, 2021·International Journal of Molecular Sciences·Matthew P GrindleAndrea N Kravats
May 1, 2021·The Journal of Physical Chemistry. B·Gennady M Verkhivker, Luisa Di Paola
Apr 24, 2020·Journal of Chemical Theory and Computation·Farzaneh JalalypourCanan Atilgan
Jan 30, 2018·Journal of Chemical Information and Modeling·David L PenklerÖzlem Tastan Bishop
Aug 17, 2021·Machine Learning: Science and Technology·Hao TianPeng Tao
Jan 20, 2021·The Journal of Physical Chemistry. B·Aysima HacisuleymanBurak Erman

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