Dissecting Structure-Encoded Determinants of Allosteric Cross-Talk between Post-Translational Modification Sites in the Hsp90 Chaperones

Abstract Post-translational modifications (PTMs) represent an important regulatory instrument that modulates structure, dynamics and function of proteins. The large number of PTM sites in the Hsp90 proteins that are scattered throughout different domains indicated that synchronization of multiple PT...

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Autores principales:	Gabrielle Stetz, Amanda Tse, Gennady M. Verkhivker
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d6af41aba02a4784a6bd7c9669bd2512
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spelling	oai:doaj.org-article:d6af41aba02a4784a6bd7c9669bd25122021-12-02T11:40:17ZDissecting Structure-Encoded Determinants of Allosteric Cross-Talk between Post-Translational Modification Sites in the Hsp90 Chaperones10.1038/s41598-018-25329-42045-2322https://doaj.org/article/d6af41aba02a4784a6bd7c9669bd25122018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25329-4https://doaj.org/toc/2045-2322Abstract Post-translational modifications (PTMs) represent an important regulatory instrument that modulates structure, dynamics and function of proteins. The large number of PTM sites in the Hsp90 proteins that are scattered throughout different domains indicated that synchronization of multiple PTMs through a combinatorial code can be invoked as an important mechanism to orchestrate diverse chaperone functions and recognize multiple client proteins. In this study, we have combined structural and coevolutionary analysis with molecular simulations and perturbation response scanning analysis of the Hsp90 structures to characterize functional role of PTM sites in allosteric regulation. The results reveal a small group of conserved PTMs that act as global mediators of collective dynamics and allosteric communications in the Hsp90 structures, while the majority of flexible PTM sites serve as sensors and carriers of the allosteric structural changes. This study provides a comprehensive structural, dynamic and network analysis of PTM sites across Hsp90 proteins, identifying specific role of regulatory PTM hotspots in the allosteric mechanism of the Hsp90 cycle. We argue that plasticity of a combinatorial PTM code in the Hsp90 may be enacted through allosteric coupling between effector and sensor PTM residues, which would allow for timely response to structural requirements of multiple modified enzymes.Gabrielle StetzAmanda TseGennady M. VerkhivkerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-19 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gabrielle Stetz Amanda Tse Gennady M. Verkhivker Dissecting Structure-Encoded Determinants of Allosteric Cross-Talk between Post-Translational Modification Sites in the Hsp90 Chaperones
description	Abstract Post-translational modifications (PTMs) represent an important regulatory instrument that modulates structure, dynamics and function of proteins. The large number of PTM sites in the Hsp90 proteins that are scattered throughout different domains indicated that synchronization of multiple PTMs through a combinatorial code can be invoked as an important mechanism to orchestrate diverse chaperone functions and recognize multiple client proteins. In this study, we have combined structural and coevolutionary analysis with molecular simulations and perturbation response scanning analysis of the Hsp90 structures to characterize functional role of PTM sites in allosteric regulation. The results reveal a small group of conserved PTMs that act as global mediators of collective dynamics and allosteric communications in the Hsp90 structures, while the majority of flexible PTM sites serve as sensors and carriers of the allosteric structural changes. This study provides a comprehensive structural, dynamic and network analysis of PTM sites across Hsp90 proteins, identifying specific role of regulatory PTM hotspots in the allosteric mechanism of the Hsp90 cycle. We argue that plasticity of a combinatorial PTM code in the Hsp90 may be enacted through allosteric coupling between effector and sensor PTM residues, which would allow for timely response to structural requirements of multiple modified enzymes.
format	article
author	Gabrielle Stetz Amanda Tse Gennady M. Verkhivker
author_facet	Gabrielle Stetz Amanda Tse Gennady M. Verkhivker
author_sort	Gabrielle Stetz
title	Dissecting Structure-Encoded Determinants of Allosteric Cross-Talk between Post-Translational Modification Sites in the Hsp90 Chaperones
title_short	Dissecting Structure-Encoded Determinants of Allosteric Cross-Talk between Post-Translational Modification Sites in the Hsp90 Chaperones
title_full	Dissecting Structure-Encoded Determinants of Allosteric Cross-Talk between Post-Translational Modification Sites in the Hsp90 Chaperones
title_fullStr	Dissecting Structure-Encoded Determinants of Allosteric Cross-Talk between Post-Translational Modification Sites in the Hsp90 Chaperones
title_full_unstemmed	Dissecting Structure-Encoded Determinants of Allosteric Cross-Talk between Post-Translational Modification Sites in the Hsp90 Chaperones
title_sort	dissecting structure-encoded determinants of allosteric cross-talk between post-translational modification sites in the hsp90 chaperones
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/d6af41aba02a4784a6bd7c9669bd2512
work_keys_str_mv	AT gabriellestetz dissectingstructureencodeddeterminantsofallostericcrosstalkbetweenposttranslationalmodificationsitesinthehsp90chaperones AT amandatse dissectingstructureencodeddeterminantsofallostericcrosstalkbetweenposttranslationalmodificationsitesinthehsp90chaperones AT gennadymverkhivker dissectingstructureencodeddeterminantsofallostericcrosstalkbetweenposttranslationalmodificationsitesinthehsp90chaperones
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Dissecting Structure-Encoded Determinants of Allosteric Cross-Talk between Post-Translational Modification Sites in the Hsp90 Chaperones

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