Cardiolipin membranes drive Myosin VI activation, oligomerization, and processive cargo transport

• 成果类型: Article
• 署名作者: Montanarella, Antonino F.; Hundt, Nikolas; Keim, Dominik; Venczel, Aron; Zierhut, Felix; Langnickel, Simon; Graw, Andreas; Kroess, Markus; Dietrich, Johannes; Saczko, Dario; Veigel, Claudia
• 署名单位: University of Munich; University of Munich
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12691
• DOI: 10.1073/pnas.2501022122
• 发表日期: 2025-06-03
• 关键词: hand-over-hand; lever arm; binding partners; motor; dimerization; autophagy; ORGANIZATION; mechanism; tracking; calcium

摘要

Mitochondrial damage determines cell fate, leading to mitochondrial autophagy or cellular apoptosis in health and disease. The molecular mechanisms and role of the acto-myosin cytoskeleton regulating mitochondrial clearance and membrane remodeling are critical in neurodegenerative disease progression including Alzheimer, but remain unclear. To investigate the potential link between full-length Myosin VI (FL-Myo6) recruitment and exposure of the mitochondria-specific lipid cardiolipin (CL), here we adapted a combination of molecular biology, biochemical, high-resolution fluorescence and interferometric light-scattering techniques. We developed analysis tools to reveal the structural Myo6-CL interaction sites, Myo6-oligomerization interfaces and mechanical properties. We found that CL activates backfolded FL-Myo6 and induces Myo6-oligomerization. Myo6 bound to CL cargo-vesicles in vitro mediates processive runs over >500 nm at >90 nm s-1. We propose a model how CL-interaction regulates backfolded Myo6 activation into a highly processive cargo-bound motor.