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HspB1 phosphorylation regulates its intramolecular dynamics and mechanosensitive molecular chaperone interaction with filamin C

Collier, Miranda P.; Alderson, T. Reid; de Villiers, Carin P.; Nicholls, Daisy; Gastall, Heidi Y.; Allison, Timothy M.; Degiacomi, Matteo T.; Jiang, He; Mlynek, Georg; Fürst, Dieter O.; van der Ven, Peter F.M.; Djinovic-Carugo, Kristina; Baldwin, Andrew J.; Watkins, Hugh; Gehmlich, Katja; Benesch, Justin L.P.

HspB1 phosphorylation regulates its intramolecular dynamics and mechanosensitive molecular chaperone interaction with filamin C Thumbnail


Authors

Miranda P. Collier

T. Reid Alderson

Carin P. de Villiers

Daisy Nicholls

Heidi Y. Gastall

Timothy M. Allison

He Jiang

Georg Mlynek

Dieter O. Fürst

Peter F.M. van der Ven

Kristina Djinovic-Carugo

Andrew J. Baldwin

Hugh Watkins

Katja Gehmlich

Justin L.P. Benesch



Abstract

Mechanical force–induced conformational changes in proteins underpin a variety of physiological functions, typified in muscle contractile machinery. Mutations in the actin-binding protein filamin C (FLNC) are linked to musculo- skeletal pathologies characterized by altered biomechanical properties and sometimes aggregates. HspB1, an abundant molecular chaperone, is prevalent in striated muscle where it is phosphorylated in response to cues including mechanical stress. We report the interaction and up-regulation of both proteins in three mouse models of biomechanical stress, with HspB1 being phosphorylated and FLNC being localized to load-bearing sites. We show how phosphorylation leads to increased exposure of the residues surrounding the HspB1 phosphosite, facili - tating their binding to a compact multidomain region of FLNC proposed to have mechanosensing functions. Steered unfolding of FLNC reveals that its extension trajectory is modulated by the phosphorylated region of HspB1. This may represent a posttranslationally regulated chaperone-client protection mechanism targeting over-extension during mechanical stress.

Citation

Collier, M. P., Alderson, T. R., de Villiers, C. P., Nicholls, D., Gastall, H. Y., Allison, T. M., …Benesch, J. L. (2019). HspB1 phosphorylation regulates its intramolecular dynamics and mechanosensitive molecular chaperone interaction with filamin C. Science Advances, 5(5), Article eaav8421. https://doi.org/10.1126/sciadv.aav8421

Journal Article Type Article
Acceptance Date Apr 16, 2019
Online Publication Date May 22, 2019
Publication Date May 22, 2019
Deposit Date May 23, 2019
Publicly Available Date May 23, 2019
Journal Science Advances
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 5
Issue 5
Article Number eaav8421
DOI https://doi.org/10.1126/sciadv.aav8421

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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
Copyright © 2019
The
Authors, some
rights reserved;
exclusive licensee
American Association
for the Advancement
of Science. No claim to
original U.S.
Government
Works. Distributed
under a Creative
Commons Attribution
License 4.0 (CC BY).





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