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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. Filamin C is a key actin-binding protein involved in cardiomyopathies and musculoskeletal disorders. Here, Wang et al reveal that it interacts with the heat shock protein HSPB7 under biomechanical stress, forming a stable hetero-dimer which is regulated by phosphorylation.

Cryptochromes are flavoproteins with a number of established and proposed biological functions based on their sensitivity to light. Amongst the latter is the possibility that cryptochromes mediate the geomagnetic compass sense used by migratory birds as a navigational cue. This hypothesis rests on a magnetically sensitive photochemical reaction of the flavin chromophore in which a series of electron transfers within the protein scaffold ultimately generates a signal propagated within the central nervous system of the animal. Although there is a good understanding of the photochemistry and the electron transfer pathway, the protein-mediated mechanisms of signal transduction are still unclear. Here we have examined the response of Drosophila melanogaster cryptochrome - DmCRY, an archetypal cryptochrome - to photochemical activation by means of molecular dynamics simulations, hydrogen-deuterium exchange mass spectrometry, and cavity ring-down spectroscopy. We were able to measure the dynamics of DmCRY at near-residue level resolution, revealing a reversible, long-lived, blue-light induced conformational change in the C-terminal tail of the protein. This putative signalling state was validated using different illumination conditions, and by examining DmCRY variants in which the electron transfer chain was disrupted by point mutation. Our results show how the photochemical behaviour of the flavin chromophore generates a state of DmCRY that may act as a key primer for modulating downstream interactions.Competing Interest StatementThe authors have declared no competing interest.

The biomechanical properties and responses of tissues underpin a variety 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. Seemingly a multi-functional protein that interacts with a variety of partners, how FLNC is regulated at the molecular level is not well understood. Here we have investigated its interaction with HSPB7, a cardiac-specific molecular chaperone whose absence is embryonically lethal. We found that FLNC and HSPB7 interact in cardiac tissue under biomechanical stress, forming a strong hetero-dimer whose structure we have solved by means of 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 rationalises on the molecular level how FLNC might switch between stabilising functions in the cell, and reveals how HSPB7 acts as a specific molecular chaperone that regulates FLNC.Competing Interest StatementThe authors have declared no competing interest.