Collier, Miranda P. and Alderson, T. Reid and de Villiers, Carin P. and Nicholls, Daisy and Gastall, Heidi Y. and Allison, Timothy M. and Degiacomi, Matteo T. and Jiang, He and Mlynek, Georg and Fürst, Dieter O. and van der Ven, Peter F. M. and Djinovic-Carugo, Kristina and Baldwin, Andrew J. and Watkins, Hugh and Gehmlich, Katja and Benesch, Justin L. P. (2019) 'HspB1 phosphorylation regulates its intramolecular dynamics and mechanosensitive molecular chaperone interaction with filamin C.', Science Advances, 5 (5). eaav8421.
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.
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|Publisher Web site:||https://doi.org/10.1126/sciadv.aav8421|
|Publisher 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).|
|Date accepted:||16 April 2019|
|Date deposited:||23 May 2019|
|Date of first online publication:||22 May 2019|
|Date first made open access:||No date available|
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