William J. Lehman, Ph.D.
Professor and Vice Chair of Pharmacology, Physiology & Biophysics
Research
We take a structural approach to study the assembly and function of actin-containing thin filaments in striated and smooth muscles. We also investigate thin filament architecture in non-muscle cells. Our principal goals are (1) to analyze and elucidate the mechanisms of thin filament-linked regulation of muscle contraction and (2) to determine the role of tropomyosin as the thin filament gatekeeper controlling access of actin-binding proteins onto actin filaments, thus controlling cytoskeletal function. To accomplish these goals, we use a combination of molecular biology, electron microscopy, and image reconstruction to better understand the structural interactions and dynamics of protein components of isolated and reconstituted thin filaments.
We also characterize thin filament components using state-of-the-art computer simulation techniques involving Molecular Dynamics (MD) and Energy Landscape protocols. To date, our EM analysis of thin filament proteins and the results of the in silico computational procedure have been mutually supportive. In a number of instances, MD simulations and energy landscapes have yielded insights not always easily obtained experimentally.
We combine our studies on native thin filament components with corresponding ones on mutants to better understand abnormal filament function in myopathic disease processes. We also develop drugs to fit within pockets found in tropomyosin to readjust normal and aberrant thin filament on-off switching.