An integrated picture of the structural pathways controlling the heart performance

Abstract

ABSTRACTRegulation of heart function is attributed to a dual filament mechanism: (i) the Ca2+-dependent structural changes in the regulatory proteins of the thin, actin-containing filament making actin available for myosin motor attachment1, and (ii) the release of motors from their folded (OFF) state on the surface of the thick filament2allowing them to attach and pull the actin filament. Thick filament mechanosensing is thought to control the number of motors switching ON in relation to the systolic performance3, but its molecular basis is still unknown. Here high spatial resolution X-ray diffraction data from electrically paced rat trabeculae and papillary muscles call for a revision of the mechanosensing hypothesis and provide a molecular explanation of the modulation of heart performance also in light of the recent cryo-EM thick filament structure4, 5. We find that upon stimulation titin activation6triggers structural changes in the thick filament that switch motors ON throughout the filament within ∼½ the maximum systolic force. These structural changes also drive MyBP-C N-terminus to bind actin7promoting first motor attachments from the central 1/3 of the half-thick filament. Progression of attachments towards the periphery of half-thick filament with increase in systolic force is carried on by near-neighbour cooperative thin filament activation by attached motors8. The identification of the roles of MyBP-C, titin, thin and thick filaments in heart regulation enables their targeting for potential therapeutic interventions.