David M. Warshaw, Ph.D.
Professor and Chair
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.
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.
Sckolnick M, Krementsova EB, Warshaw DM, Trybus KM (2016) Tropomyosin isoforms bias actin track selection by vertebrate myosin Va. Mol Biol Cell : .
Heaslip AT, Nelson SR, Warshaw DM (2016) Dense granule trafficking in Toxoplasma gondii requires a unique class 27 myosin and actin filaments. Mol Biol Cell 27(13): 2080-9.
Warshaw DM (2016) HEART DISEASE. Throttling back the heart’s molecular motor. Science 351(6273): 556-7.
Previs MJ, Mun JY, Michalek AJ, Previs SB, Gulick J, Robbins J, Warshaw DM, Craig R (2016) Phosphorylation and calcium antagonistically tune myosin-binding protein C’s structure and function. Proc Natl Acad Sci U S A 113(12): 3239-44.
Michalek AJ, Kennedy GG, Warshaw DM, Ali MY (2015) Flexural Stiffness of Myosin Va Subdomains as Measured from Tethered Particle Motion. J Biophys 2015: 465693.
Previs MJ, Prosser BL, Mun JY, Previs SB, Gulick J, Lee K, Robbins J, Craig R, Lederer WJ, Warshaw DM (2015) Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling. Sci Adv 1(1): .
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.