Membrane-induced Lever Arm Expansion Allows Myosin VI to Walk with Large and Variable Step Sizes

Abstract

Background: Myosin VI plays diverse cellular roles ranging from intracellular transport to mechanical anchor. Results: Myosin VI LAE undergoes reversible, lipid membrane-dependent conformational changes from compact bundle fold to extended rod shape. Conclusion: LAE functions as the "knee joint" of myosin VI and provides both space and flexibility for stepping. Significance: The membrane-induced expansion of LAE provides a mechanistic base for myosin VI to walk with large and variable step sizes.

Various Themes of Myosin Regulation

“…The myosin-6 heavy chain contains a lever arm extension that adopts a stable and monomeric three-helix bundle in solution [162, 163]. Exposure to lipid membranes triggers a reversible conformational change of this compact three-helix bundle to a rod-shaped structure.…”

“…Exposure to lipid membranes triggers a reversible conformational change of this compact three-helix bundle to a rod-shaped structure. A proposed kiss-and-run model suggest the synergistic action of adaptor-regulated dimerization and cargo-vesicle induced unfolding of the three-helix bundle to render monomeric myosin-6 into a dimeric, processive transporter with large and variable step size [162, 164]. In line with this finding, structural changes in the myosin-6 tail are also induced by Ca 2+ -dependent PtdIns(4,5)P 2 -binding [165].…”

“…As outlined in greater detail above, myosin-6 binds lipids via a three-helix bundle immediately preceding the CBD [162]. A proposed kiss-and-run model suggests that lipid binding of the three-helix bundle to cargo vesicles increases the local pool of monomeric myosin-6 at the membrane, thereby facilitating the cargo-induced dimerization [164].…”

Structural Basis of Cargo Recognition by Unconventional Myosins in Cellular Trafficking

“…Myosin-VI contains a ∼80-aa helical region known as lever arm extension (LAE). It folds into a three-helix bundle (∼3 nm in length) in the absence of cargo binding but extends into a semi-rigid, elongated helix 6-9 nm in length upon cargo binding (37,38). This cargo binding-induced LAE contributes to the very large step size (∼36 nm) of myosin-VI (37,38).…”

“…It folds into a three-helix bundle (∼3 nm in length) in the absence of cargo binding but extends into a semi-rigid, elongated helix 6-9 nm in length upon cargo binding (37,38). This cargo binding-induced LAE contributes to the very large step size (∼36 nm) of myosin-VI (37,38). Myosin-Ic, and likely other short-tailed myosin-Is including myosin-Ia, Ib, Id, Ig and Ih, contain an atypical helical domain (known as the post-IQ region, see below for details) following the canonical IQ motifs.…”