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Image of myosin-actin interaction revealed in cover story of Molecular Cell

Scientists from the Burnham Institute for Medical Research and the University of Vermont have captured the first 3-dimensional (3D) atomic-resolution images of the motor protein myosin V as it "walks" along other proteins, revealing new structural insights that advance the current model of protein motility and muscle contraction. The culmination of four years of work, this collaboration among biochemists and structural biologists was selected as the cover story for the September issue of the scientific journal Molecular Cell.

The Burnham team, led by Dorit Hanein, Ph.D., was the first to reveal the 3D representation of myosin V "walking" along actin filament, a key protein involved in motility and muscle contraction. Using electron-cryo microscopy to take 3D snapshots of myosin V and actin interacting, researchers were able to see myosin V moving along the actin substrate in a "natural state." Previous 2D models have been based on staining or other treatment of the myosin that might alter the complex's natural mechanism of action.

Myosins are a large family of motor proteins that interact with actin filaments for motor movement and muscle contraction. Myosin V is the workhorse of the myosin protein family. It exists to ferry a cargo of proteins needed in a specific place at a specific time. Fueled by hydrolysis -- the process of converting the molecule adenosine triphosphate (ATP) into energy -- myosin V travels in one direction using actin as a track to deliver its payload of cell vesicles and organelles. Myosin V is also involved in transporting proteins that signal and communicate with other cells.

Myosin V has a two-chained "tail" that diverges to form two "heads" that bind to specific grooves on actin and walk hand over hand along the track, similar to the way a child moves along the monkey bars in a playground. Myosin V differs from the other myosin family proteins in that it is able to sustain this processive motion, enduring man y hydrolysis cycles. The other myosins grab on tightly to actin and release after one hydrolysis cycle.

"This study required a different way of thinking about image analysis. This is the first time we were able to structurally visualize the weak binding states of actin and myosin, not interpolated from crystal structures, and not interpolated from biophysical methods," said Dr. Hanein. "We were able to see structural changes in the myosin lever arm as well as in the actin interface as it propagates through the hydrolysis cycle."

Structural information from previous studies provided information about parts of this process, but until the present collaboration, visualizing Myosin V in its weakly bound state to actin had not been possible. The Hanein group captured snapshots of Myosin V at several points during a hydrolysis cycle. Their use of electron cryo-microscopy made it possible to visualize flexible structural domains, which tether the Myosin V, helping to keep the protein on its actin track through the weak binding phase of the processive movement.

The detailed molecular knowledge of how myosin interacts through the hydrolysis cycle with actin provides an exciting new research template onto which scientists can design new sets of experiments to further refine the myosin-actin binding region and to correlate it with loss or gain of function. The precise characterization of this myosin-actin interface is critical, evident by the way a single amino acid change in myosin leads to familial hypertrophic cardiomyopathy (FHC), an undetectable condition resulting in death by sudden cardiac arrest in otherwise healthy young adults.

Contributors to this work include: Niels Volkmann, Ph.D., assistant professor and first author on this publication, Dorit Hanein, Ph.D., associate professor, Hong-Jun Liu and Larnele Hazelwood from the Burnham Institute for Medical Research; and Kathleen M. Trybus, Ph.D., Susan Lowey, Ph.D., and Elena B. Kremen stova, Ph.D., from the Department of Molecular Physiology and Biophysics at the University of Vermont.

Functional, biochemical assays were conducted by collaborators from the University of Vermont, directed by Kathleen Trybus, Ph.D.


Source:Burnham Institute

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