biostudies-literatureWang ZLeverhulme TrustBritish Heart FoundationDeutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft (German Research Foundation)Medical Research CouncilRoyal SocietyWellcome Trust4090https://www.ebi.ac.uk/biostudies/studies/S-EPMC12046049biostudies-literatureUnknown16(1)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 oNature communicationsFilamin C dimerisation is regulated by HSPB7.PMC12046049FOR 2743 - FU339/11-2FU339/13-1MR/V009540/1RE/13/1/30181FS/12/40/29712RPG-2021-246FOR 2743, project P09 (WA1598/6)201543/B/16/ZAA/18/2/34218Alderson TRCao GSaman DZimmermann JCollier MPQiu XBroadway-Stringer SNg JZYBrem JWang ZHochberg GKABolla JRAzad AJMcDonough MADjinovic-Carugo KSen NRobinson CVSong HSchofield CJRabe PGehmlich KAllison TMHooper CFurst DOWarscheid BDegiacomi MTBenesch JLPfalseFilamin 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 o2025-01-01T00:00:00Z2025 May2026-06-02T20:56:29.582Z2025-07-06T03:05:52.641ZS-EPMC120460494031238110.1038/s41467-025-58889-x