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

Research output: Contribution to journalArticle

Authors

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

Colleges, School and Institutes

External organisations

  • Department of Chemistry, Physical and Theoretical Chemistry Laboratory
  • Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, A-1030 Vienna, Austria
  • Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, D53121 Bonn, Germany
  • University of Oxford

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 musculoskeletal 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 localized to load-bearing sites. We show how phosphorylation leads to increased exposure of the residues surrounding the HspB1 phosphosite, facilitating their binding to a compact multi-domain 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 post-translationally regulated chaperone-client protection mechanism targeting over-extension during mechanical stress.

Details

Original languageEnglish
Article numbereaav8421
JournalScience Advances
Volume5
Issue number5
Publication statusPublished - 22 May 2019