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.

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., Degiacomi, M. T., Jiang, H., Mlynek, G., Fürst, D. O., van der Ven, P. F., Djinovic-Carugo, K., Baldwin, A. J., Watkins, H., Gehmlich, K., & 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
• Public URL: https://durham-repository.worktribe.com/output/1295844