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Filamin C dimerisation is regulated by HSPB7

Author

Listed:
  • Zihao Wang

    (University of Oxford
    University of Oxford
    University of Leeds)

  • Guodong Cao

    (University of Oxford
    University of Oxford)

  • Miranda P. Collier

    (University of Oxford
    University of Oxford)

  • Xingyu Qiu

    (University of Oxford
    University of Oxford)

  • Sophie Broadway-Stringer

    (University of Birmingham)

  • Dominik Šaman

    (University of Oxford
    University of Oxford)

  • Jediael Z. Y. Ng

    (Max Planck Institute for Terrestrial Microbiology)

  • Navoneel Sen

    (University of Oxford
    University of Oxford)

  • Amar J. Azad

    (University of Birmingham
    Universitätsmedizin Berlin)

  • Charlotte Hooper

    (University of Oxford)

  • Johannes Zimmermann

    (University of Würzburg)

  • Michael A. McDonough

    (Chemistry Research Laboratory)

  • Jürgen Brem

    (Chemistry Research Laboratory
    Babes-Bolyai University)

  • Patrick Rabe

    (Chemistry Research Laboratory
    Harwell Science and Innovation Campus)

  • Haigang Song

    (University of Oxford
    University of Oxford)

  • T. Reid Alderson

    (University of Oxford
    University of Oxford
    Institute of Structural Biology
    Bavarian NMR Center)

  • Christopher J. Schofield

    (Chemistry Research Laboratory
    University of Oxford)

  • Jani R. Bolla

    (University of Oxford)

  • Kristina Djinovic-Carugo

    (European Molecular Biology Laboratory
    University of Vienna)

  • Dieter O. Fürst

    (University of Bonn)

  • Bettina Warscheid

    (University of Würzburg)

  • Matteo T. Degiacomi

    (Durham University
    University of Edinburgh)

  • Timothy M. Allison

    (University of Canterbury)

  • Georg K. A. Hochberg

    (Max Planck Institute for Terrestrial Microbiology
    Philipps-University Marburg
    Philipps-University Marburg)

  • Carol V. Robinson

    (University of Oxford
    University of Oxford)

  • Katja Gehmlich

    (University of Birmingham
    University of Oxford)

  • Justin L. P. Benesch

    (University of Oxford
    University of Oxford)

Abstract

The biomechanical properties and responses of tissues underpin a variety important of physiological functions and pathologies. In striated muscle, the actin-binding protein filamin C (FLNC) is a key protein whose variants causative for a wide range of cardiomyopathies and musculoskeletal pathologies. FLNC is a multi-functional protein that interacts with a variety of partners, however, how it is regulated at the molecular level is not well understood. Here we investigate its interaction with HSPB7, a cardiac-specific molecular chaperone whose absence is embryonically lethal. We find that FLNC and HSPB7 interact in cardiac tissue under biomechanical stress, forming a strong hetero-dimer whose structure we solve by X-ray crystallography. Our quantitative analyses show that the hetero-dimer out-competes the FLNC homo-dimer interface, potentially acting to abrogate the ability of the protein to cross-link the actin cytoskeleton, and to enhance its diffusive mobility. We show that phosphorylation of FLNC at threonine 2677, located at the dimer interface and associated with cardiac stress, acts to favour the homo-dimer. Conversely, phosphorylation at tyrosine 2683, also at the dimer interface, has the opposite effect and shifts the equilibrium towards the hetero-dimer. Evolutionary analysis and ancestral sequence reconstruction reveals this interaction and its mechanisms of regulation to date around the time primitive hearts evolved in chordates. Our work therefore shows, structurally, how HSPB7 acts as a specific molecular chaperone that regulates FLNC dimerisation.

Suggested Citation

  • Zihao Wang & Guodong Cao & Miranda P. Collier & Xingyu Qiu & Sophie Broadway-Stringer & Dominik Šaman & Jediael Z. Y. Ng & Navoneel Sen & Amar J. Azad & Charlotte Hooper & Johannes Zimmermann & Michae, 2025. "Filamin C dimerisation is regulated by HSPB7," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58889-x
    DOI: 10.1038/s41467-025-58889-x
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