Filamin C dimerisation is regulated by HSPB7

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, Michael A. McDonough, Jürgen Brem, Patrick Rabe, Haigang Song, T. Reid Alderson, Christopher J. Schofield, Jani R. Bolla, Kristina Djinovic-Carugo, Dieter O. Fürst, Bettina Warscheid, Matteo T. Degiacomi, Timothy M. Allison, Georg K. A. Hochberg, Carol V. Robinson, Katja Gehmlich () and Justin L. P. Benesch ()
Additional contact information
Zihao Wang: University of Oxford
Guodong Cao: University of Oxford
Miranda P. Collier: University of Oxford
Xingyu Qiu: University of Oxford
Sophie Broadway-Stringer: University of Birmingham
Dominik Šaman: University of Oxford
Jediael Z. Y. Ng: Max Planck Institute for Terrestrial Microbiology
Navoneel Sen: University of Oxford
Amar J. Azad: University of Birmingham
Charlotte Hooper: University of Oxford
Johannes Zimmermann: University of Würzburg
Michael A. McDonough: Chemistry Research Laboratory
Jürgen Brem: Chemistry Research Laboratory
Patrick Rabe: Chemistry Research Laboratory
Haigang Song: University of Oxford
T. Reid Alderson: University of Oxford
Christopher J. Schofield: Chemistry Research Laboratory
Jani R. Bolla: University of Oxford
Kristina Djinovic-Carugo: European Molecular Biology Laboratory
Dieter O. Fürst: University of Bonn
Bettina Warscheid: University of Würzburg
Matteo T. Degiacomi: Durham University
Timothy M. Allison: University of Canterbury
Georg K. A. Hochberg: Max Planck Institute for Terrestrial Microbiology
Carol V. Robinson: University of Oxford
Katja Gehmlich: University of Birmingham
Justin L. P. Benesch: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58889-x

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