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Wang, Z.* ; Cao, G.* ; Collier, M.P.* ; Qiu, X.* ; Broadway-Stringer, S.* ; Šaman, D.* ; Ng, J.Z.Y.* ; Sen, N.* ; Azad, A.J.* ; Hooper, C.* ; Zimmermann, J.* ; McDonough, M.A.* ; Brem, J.* ; Rabe, P.* ; Song, H.* ; Alderson, T.R. ; Schofield, C.J.* ; Bolla, J.R.* ; Djinovic-Carugo, K.* ; Fürst, D.O.* ; Warscheid, B.* ; Degiacomi, M.T.* ; Allison, T.M.* ; Hochberg, G.K.A.* ; Robinson, C.V.* ; Gehmlich, K.* ; Benesch, J.L.P.*

Filamin C dimerisation is regulated by HSPB7.

Nat. Commun. 16:4090 (2025)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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 type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 16, Issue: 1, Pages: , Article Number: 4090 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
Grants Wellcome Trust