title: Membrane-induced lever arm expansion allows myosin VI to walk with large and variable step sizes.
abstract: Myosin VI, the only known minus-ended actin filament-dependent motor, plays diverse cellular roles both as a processive motor and as a mechanical anchor. Although myosin VI has a short lever arm containing only one "IQ-motif" and a unique insertion for CaM binding, the motor walks with large and variable step sizes of ∼30-36 nm. Here, we show that the previously predicted coiled-coil domain immediately following the IQ-motifs (referred to as the lever arm extension (LAE)) adopts a stable monomeric, three-helix bundle fold in solution. Importantly, the LAE can undergo reversible, lipid membrane-dependent conformational changes. Upon exposure to lipid membranes, the LAE adopts a partially extended rod shape, and the removal of lipids from the LAE converts it back into the compact helix bundle structure. Molecular dynamics simulations indicate that lipid membrane binding may initiate unfolding and thereby trigger the LAE expansion. This reversible, lipid membrane-dependent expansion of the LAE provides a mechanistic base for myosin VI to walk with large and variable step sizes.
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Yu
authors.affiliation: National Laboratory of Biomacromolecules, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China; Laboratory of Noncoding RNA, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Lou
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Pan
authors.affiliation: National Laboratory of Biomacromolecules, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China. Electronic address: wfeng@ibp.ac.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Center of Systems Biology and Human Health, School of Science and Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Electronic address: mzhang@ust.hk.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002417:Cattle; D002462:Cell Membrane / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D056004:Molecular Dynamics Simulation; D018995:Myosin Heavy Chains / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: C089785:myosin VI; D018995:Myosin Heavy Chains