An integrated picture of the structural pathways controlling the heart performance

• 成果类型: Article
• 署名作者: Morotti, Ilaria; Caremani, Marco; Marcello, Matteo; Pertici, Irene; Squarci, Caterina; Bianco, Pasquale; Narayanan, Theyencheri; Piazzesi, Gabriella; Reconditi, Massimo; Lombardi, Vincenzo; Linari, Marco
• 署名单位: University of Florence; University of Florence; European Synchrotron Radiation Facility (ESRF); University of Florence
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12518
• DOI: 10.1073/pnas.2410893121
• 发表日期: 2024-12-10
• 关键词: binding-protein-c; sarcomere-length dependence; x-ray-diffraction; cardiac myosin; skeletal-muscle; striated-muscle; filament structure; working stroke; thick filament; atomic model

摘要

The regulation 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 attachment, and ii) the release of motors from their folded (OFF) state on the surface of the thick filament allowing 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 performance, but its molecular basis is still controversial. Here, we use high spatial resolution X-ray diffraction data from electrically paced rat trabeculae and papillary muscles to provide a molecular explanation of the modulation of heart performance that calls for a revision of the mechanosensing hypothesis. We find that upon stimulation, titin-mediated structural changes in the thick filament switch motors ON throughout the filament within similar to 1/2 the maximum systolic force. These structural changes also drive Myosin Binding Protein-C (MyBP-C) to promote first motor attachments to actin from the central 1/3 of the half-thick filament. Progression of attachments toward the periphery of half-thick filament with increase in systolic force is carried on by near-neighbor cooperative thin filament activation by attached motors. The identification of the roles of MyBP-C, titin, thin and thick filaments in heart regulation enables their targeting for potential therapeutic interventions.