Hsp70 belongs to a family of molecular chaperones ubiquitous through organisms that assist client protein folding and prevent aggregation. It works through a tightly ATP-regulated allosteric cycle mechanism, which organizes its two NBD and SBD into alternate open and closed arrangements that facilitate loading and unloading of client proteins. The two cytosolic human isoforms Hsc70 and HspA1 are relevant targets for neurodegenerative diseases and cancer. Illuminating the molecular details of Hsp70 functional dynamics is essential to rationalize differences among the well-characterized bacterial homologue DnaK and the less explored human forms and develop subtype- or species-selective allosteric drugs. We present here a molecular dynamics-based analysis of the conformational dynamics of HspA1. By using an "allosterically impaired" mutant for comparison, we can reconstruct the impact of the ADP-ATP swap on interdomain contacts and dynamic coordination in full-length HspA1, supporting previous predictions that were, however, limited to the NBD. We model the initial onset of the conformational cycle by proposing a sequence of structural steps, which reveal the role of a specific human sequence insertion at the linker, and a modulation of the angle formed by the two NBD lobes during the progression of docking. Our findings pinpoint functionally relevant conformations and set the basis for a selective structure-based drug discovery approach targeting allosteric sites in human Hsp70.
Exploring Mutation-Driven Changes in the ATP-ADP Conformational Cycle of Human Hsp70 by All-Atom MD Adaptive Sampling
Rinaldi, Silvia;Morra, Giulia
2024
Abstract
Hsp70 belongs to a family of molecular chaperones ubiquitous through organisms that assist client protein folding and prevent aggregation. It works through a tightly ATP-regulated allosteric cycle mechanism, which organizes its two NBD and SBD into alternate open and closed arrangements that facilitate loading and unloading of client proteins. The two cytosolic human isoforms Hsc70 and HspA1 are relevant targets for neurodegenerative diseases and cancer. Illuminating the molecular details of Hsp70 functional dynamics is essential to rationalize differences among the well-characterized bacterial homologue DnaK and the less explored human forms and develop subtype- or species-selective allosteric drugs. We present here a molecular dynamics-based analysis of the conformational dynamics of HspA1. By using an "allosterically impaired" mutant for comparison, we can reconstruct the impact of the ADP-ATP swap on interdomain contacts and dynamic coordination in full-length HspA1, supporting previous predictions that were, however, limited to the NBD. We model the initial onset of the conformational cycle by proposing a sequence of structural steps, which reveal the role of a specific human sequence insertion at the linker, and a modulation of the angle formed by the two NBD lobes during the progression of docking. Our findings pinpoint functionally relevant conformations and set the basis for a selective structure-based drug discovery approach targeting allosteric sites in human Hsp70.File | Dimensione | Formato | |
---|---|---|---|
rinaldi-et-al-2024-exploring-mutation-driven-changes-in-the-atp-adp-conformational-cycle-of-human-hsp70-by-all-atom-md.pdf
embargo fino al 02/08/2025
Descrizione: “This document is the Accepted Manuscript version of a Published Work that appeared in final form in The Journal of Physical Chemistry B, copyright © 2024 American Chemical Society, after peer review and technical editing by the publisher. To access the final edited and published work see https://soi.org/10.1021/acs.jpcb.4c03603.”
Tipologia:
Documento in Post-print
Licenza:
Altro tipo di licenza
Dimensione
6.87 MB
Formato
Adobe PDF
|
6.87 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
J. Phys. Chem. B 2024, 128, 32, 7770–7780.pdf
solo utenti autorizzati
Tipologia:
Versione Editoriale (PDF)
Licenza:
NON PUBBLICO - Accesso privato/ristretto
Dimensione
7.02 MB
Formato
Adobe PDF
|
7.02 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.