Myosin Molecular Motors



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Dr. Warshaw received his Ph.D. in Physiology and Biophysics at the University of Vermont in 1978, and continued his research studying the molecular mechanism of muscle contraction as a post-doctoral associate at the University of Massachusetts Medical School. He returned to the University of Vermont as an Assistant Professor of Molecular Physiology & Biophysics in 1983 and now is Professor and Chair of the Department. Currently, Dr. Warshaw’s lab is using state-of-the-art single molecule detection and manipulation techniques to characterize the structure and function of myosin molecular motors in normal and disease states of the cardiovascular system.

Research Description

The myosin superfamily now consists of at least 18 different classes of myosin molecular motors. These myosins interact with actin to generate force and motion that is used in a range of biological functions from muscle contraction, organelle transport, to cell division. All myosins share significant structural and functional capacities, i.e. they possess a motor domain that hydrolyzes ATP, binds actin, and is the force and motion generator. From the motor domain, a light-chain and/or calmodulin-binding domain emerges that acts like a mechanical lever to amplify small conformational changes that occur within the motor domain. The differences in both structure and function among the various myosins can provide a model system to help probe the molecular structure and function of myosin as a chemomechanical enzyme. For example, we are characterizing the molecular biophysics of myosin V, a double-headed specie, which is believed to be a vesicular transporter. This myosin has been shown to be both processive and takes large, ~40nm steps. To be processive, both heads should have a high duty ratio and be coordinated, so that forward motion can occur and that at least one head is attached to its actin track at any time to prevent the myosin and its cargo from diffusing away. Using the laser trap and single molecule fluorescence detection techniques, questions regarding the coordination between heads, what structural feature of the myosin V molecule is necessary for processivity, and how strain between the heads serves as a coordinating signal are being addressed.

Recent Publications

Heaslip AT, Nelson SR, Lombardo AT, Beck Previs S, Armstrong J, Warshaw DM (2014) Cytoskeletal Dependence of Insulin Granule Movement Dynamics in INS-1 Beta-Cells in Response to Glucose. PLoS One 9(10): e109082.

Nelson SR, Trybus KM, Warshaw DM (2014) Motor coupling through lipid membranes enhances transport velocities for ensembles of myosin Va. Proc Natl Acad Sci U S A 111(38): E3986-95.

Mukherjea M, Ali MY, Kikuti C, Safer D, Yang Z, Sirkia H, Ropars V, Houdusse A, Warshaw DM, Sweeney HL (2014) Myosin VI must dimerize and deploy its unusual lever arm in order to perform its cellular roles. Cell Rep 8(5): 1522-32.

Nelson SR, Dunn AR, Kathe SD, Warshaw DM, Wallace SS (2014) Two glycosylase families diffusively scan DNA using a wedge residue to probe for and identify oxidatively damaged bases. Proc Natl Acad Sci U S A 111(20): E2091-9.

Lee AJ, Warshaw DM, Wallace SS (2014) Insights into the glycosylase search for damage from single-molecule fluorescence microscopy. DNA Repair (Amst) 20: 23-31.

Mun JY, Previs MJ, Yu HY, Gulick J, Tobacman LS, Beck Previs S, Robbins J, Warshaw DM, Craig R (2014) Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism. Proc Natl Acad Sci U S A 111(6): 2170-5.

Previs MJ, Michalek AJ, Warshaw DM (2014) Molecular modulation of actomyosin function by cardiac myosin-binding protein C. Pflugers Arch 466(3): 439-44.

View all Warshaw publications here.


David Warshaw, Ph.D.

David
Warshaw, Ph.D.

Professor and Chair
Department of Molecular Physiology & Biophysics

 

802-656-4300
Office: HSRF 116
Lab: HSRF 115

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