Filamin C dimerisation is regulated by HSPB7

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.

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Publication Details

Journal
Nature Communications
Published
2025-05-01
DOI
https://doi.org/10.1038/s41467-025-58889-x
Citations
4
Primary Topic
Endoplasmic Reticulum Stress and Disease
Type
article
Field-Weighted Citation Impact
4.61

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article

Filamin C dimerisation is regulated by HSPB7

Guodong Cao, Carol V. Robinson, Patrick Rabe, Katja Gehmlich et al.
4 citations
Nature Communications
Endoplasmic Reticulum Stress and Disease
4.61
article

Filamin C dimerisation is regulated by HSPB7

Guodong Cao, Carol V. Robinson, Patrick Rabe, Katja Gehmlich, T. Reid Alderson, Haigang Song, Jediael Z. Y. Ng, Bettina Warscheid, Amar J. Azad, M.A. McDonough, Timothy M. Allison, Christopher John Schofield, Charlotte Hooper, M Collier, Navoneel Sen, Xingyu Qiu, Sophie Broadway‐Stringer, Jürgen Brem, Dominik Šaman, Zihao Wang, Matteo T. Degiacomi, Johannes P. Zimmermann, Georg Hochberg, Kristina Djinović‐Carugo, Jani Reddy Bolla, Dieter O. Fürst, Justin L. P. Benesch
article en
4 citations

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.

Nature CommunicationsVol. 16(1)
University of Vienna (AT), University of Leeds (GB), University of Bonn (DE), Philipps University of Marburg (DE), University of Canterbury (NZ), Durham University (GB), University of Würzburg (DE), Diamond Light Source (GB), Max Perutz Labs (AT), Helmholtz Zentrum München (DE), Babeș-Bolyai University (RO), British Heart Foundation (GB), University of Oxford (GB), European Molecular Biology Laboratory (FR), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Loewe Center for Synthetic Microbiology (DE), Science Oxford (GB), Max Planck Institute for Terrestrial Microbiology (DE), Technical University of Munich (DE), University of Birmingham (GB), University of Edinburgh (GB)
Wellcome, Wellcome Trust, Diamond Light Source, British Heart Foundation, Leverhulme Trust, Royal Society, Deutsche Forschungsgemeinschaft, Medical Research Council
Openalex Percentile: Top 6%
Endoplasmic Reticulum Stress and Disease
4.61
DOIOpen Access PDFOpenAlex
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