Switch between large hand-over-hand and small inchworm-like steps in myosin VI

Area of Science:

• Molecular Biology
• Cellular Biophysics

Background:

• Biological motor proteins typically exhibit predictable step sizes based on their structure.
• Myosin VI presents a notable exception, displaying larger and more varied step sizes than predicted by its short lever arms.

Purpose of the Study:

• To resolve the discrepancy between predicted and observed step sizes of Myosin VI.
• To elucidate the underlying mechanisms responsible for Myosin VI's large and variable step sizes.

Main Methods:

• High-sensitivity nanoimaging was employed to monitor quantum dots (Qdots) and gold nanoparticles attached to Myosin VI motor domains.
• Analysis focused on quantifying step sizes and their distribution during motor activity.

Main Results:

• Myosin VI exhibits two distinct step sizes: a large step of 72 nm and a small step of 44 nm.
• The large step size is attributed to an extended and rigid lever arm, while variability arises from two distinct tilt angles (pre- and postpowerstroke states).
• Small step frequency increases with ADP, suggesting an ADP-dependent mechanism.

Conclusions:

• Myosin VI utilizes two stepping mechanisms: a hand-over-hand mechanism for large steps and an inchworm-like mechanism for small steps.
• The motor dynamically switches between these mechanisms in a strain-sensitive and ADP-dependent manner.
• This adaptability allows Myosin VI to perform diverse cellular roles, including vesicle transport and membrane anchoring.