William J. Lehman, Ph.D.
Professor of Physiology & Biophysics
- Title Professor of Physiology & Biophysics
- Office W408E
- Email firstname.lastname@example.org
- Phone (617) 358-8484
- Education B.S. State University of New York at Stony Brook
Ph.D. Princeton University
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.
Our laboratory provided fundamental structural evidence supporting the steric-blocking mechanism of muscle regulation by identifying the positions assumed by tropomyosin on actin in the presence and the absence of Ca2+ using cryo-electron microscopy and negative staining. We also demonstrated that on activation tropomyosin moves away from myosin cross-bridge binding sites on actin in two steps, one induced by Ca2+ binding to troponin and a second induced by the binding of myosin to actin. In addition, we showed that the shape of tropomyosin is designed to match the contours of the Factin filament and that tropomyosin’s curved shape is semi-rigid, and thus capable of cooperative movement on thin filaments. Merging our experimental results and our computational chemistry, we developed the first all atoms model of the F-actin-tropomyosin filament. The model indicates at an atomic level how point mutations in tropomyosin associated with Hypertrophic Cardiomyopathies can lead to muscle dysfunction.
Our laboratory is continuing the above-mentioned studies to obtain even greater resolution of the processes involved in regulating contractile and cytoskeletal filaments in striated and in smooth muscle filaments. At the same time, we are investigating the structural organization of troponin on thin filaments and the changes it undergoes on binding of Ca2+. We have also engaged in studies on the structural interactions of other actin binding proteins including caldesmon, calponin, cortactin, and native and mutant dystrophin, filamin, fimbrin, fascin, leiomodin and tropomodulin, namely proteins that play important roles in the organization of the cytoskeleton in striated and smooth muscles as well as in non-muscle cells.
The contributions that we have made have had profound implications on current biomedical and translational research. For example, assays that we developed led to the discovery of myosin-phosphorylation as a regulator of smooth muscle contractility. The myosin-phosphorylation cascade is an obvious target for drug manipulation.
Vascular smooth muscle stiffness is a major contributor and leading risk factor in the development of cardiovascular dysfunction. An examination of how the smooth muscle cell actin cytoskeleton is modulated by accessory proteins to control vascular stiffness is an ongoing goal of our work.
Janco, M., M.J. Rynkiewicz, L. Li, J. Hook, E. Eiffe, A. Ghosh, T. Boecking, W. Lehman, E. Hardeman, P. Gunning (2019) Molecular integration of the anti-tropomyosin compound ATM-3507 into the coiled coil overlap region of the cancer-associated Tpm3.1. Sci. Reports 9, 11262.
Lehman, W., J.R. Moore, S.G. Campbell, M.J. Rynkiewicz (2019) The effect of tropomyosin mutations on actin-tropomyosin binding: In search of lost time. Biophys. J. 116, 2275-2284.
Lehman, W., M.J. Rynkiewicz, J.R. Moore (2019) A new twist on tropomyosin binding to actin filaments: Perspectives on thin filament function, assembly and biomechanics. J. Muscle Research Cell Motility (in press).
Kiani, F.A., W. Lehman, S. Fischer, M.J. Rynkiewicz. (2019) Spontaneous transitions of actin-bound tropomyosin towards blocked and closed states. J. Gen. Physiol. 151, 4-8.
Lehman, W. X. Li, F.A. Kiani, J.R. Moore, S.G. Campbell, S. Fischer, M.J. Rynkiewicz. (2018) Precise binding of tropomyosin on actin involves sequence-dependent variance in coiled-coil twisting. Biophys. J. 115, 1082-1092.
Farman, G.P., M.J. Rynkiewicz, M. Orzechowski, W. Lehman, J.R. Moore (2018) HCM and DCM cardiomyopathy-linked α-tropomyosin mutations influence off-state stability and crossbridge interaction on thin filaments. Arch. Biochem. Biophys. 647, 84-92.
Rynkiewicz, M.J., T. Prum, S. Hollenberg, F.A. Kiani, P.M. Fagnant, S.B. Marston, K.M. Trybus, S. Fischer, J.R. Moore, W. Lehman (2017) Tropomyosin must interact weakly with actin to effectively regulate thin filament function. Biophys. J. 113, 2444-2451.
Viswanathan, M.C., W. Schmidt, M.R. Rynkiewicz, K. Agarawal, J. Gao, J. Katz, W. Lehman, A. Cammarato (2017) Distortion of the A-triad results in contractile disinhibition and cardimyopathy. Cell Reports 20, 2612-2625.
Lehman, W. (2017) Switching muscles on and off in steps – The McKillop-Geeves threestate model of muscle regulation. Biophys. J. (in press).
Sewanan, L.R., J.R. Moore, W. Lehman, S.G. Campbell (2016) Predicting effects of tropomyosin mutations on cardiac contraction through myofilament modeling. Frontiers Physiol. 7, 473 (eCollection). PMCID:PMC5081029
Rynkiewicz, M.J., S. Fischer, W. Lehman (2016) The propensity for tropomyosin twisiting in the presence and absence of F-actin. Arch. Biochem. Biophys. 609, 51-58. PMCID:PMC5064861
Moore, J. R., S. G. Campbell, W. Lehman (2016) Structural Determinants of muscle thin filament cooperativity. Arch. Biochem. Biophys. 594, 8-17. PMCID:PMC4792785
Fischer, S., M. J. Rynkiewicz, J. R. Moore, W. Lehman (2016) Tropomyosin diffusion over actin subunits facilitates thin filament assembly. Structural Dynamics 3, 012002. PMCID:PMC4714992
Lehman, W. (2016) Thin filaments and the steric blocking model. Comprehensive Physio. 6:1043-1069. DOI:10.1002/cphy.c150030
Rynkiewicz, M. R., V. Schott, M. Orzechowski, W. Lehman, S. Fischer (2015) Electrostatic interaction map reveals a new binding position for tropomyosin on Factin. J. Muscle Res. Cell Motility (in press).
Alamo L, X. E. Li, L. M. Espinoza-Fonseca, A. Pinto, D. D. Thomas, W. Lehman, R. Padrón (2015) Tarantula myosin free head regulatory light chain phosphorylation stiffens N-terminal extension, releasing it and blocking its docking back. Mol Biosyst. 11, 2180-2189.
Schmidt W. M., W. Lehman, J. R. Moore (2015) Direct observation of tropomyosin binding to actin filaments. Cytoskeleton (Hoboken) 72, 292-303.
Jurak-Begonja A., F. G. Pluthero, W. Suphamungmee, S. Giannini, H. Christensen, R. Leung, R. W. Lo , F. Nakamura F, W. Lehman, M. Plomann, K. M. Hoffmeister, W. H. Kahr, J. H. Hartwig, H. Falet (2015) FlnA binding to PACSIN2 F-BAR domain regulates membrane tubulation in megakaryocytes and platelets. Blood. 126, 80-88.
von der Ecken J., M. Müller, W. Lehman, D. J. Manstein, P. A. Penczek, S. Raunser (2014) Structure of the F-actin-tropomyosin complex. Nature 519, 114-117.
Lehman, W., G. Medlock, X. E. Li, W. Suphamungmee, A.-Y. Tu, A. Schmidtmann, Z. Ujfalusi, S. Fischer, J. R. Moore, M. A. Geeves, & M. Regnier (2015) Phosphorylation of Ser283 Enhances the Stiffness of the Tropomyosin Head-to-Tail Overlap Domain. Arch. Biochem. Biophys. 571, 10-15.
Orzechowski, M., S. Fischer, J. R. Moore, W. Lehman, & G. P. Farman. (2014) Energy landscapes reveal the myopathic effects of tropomyosin mutations. Arch. Biochem. Biophys. 564, 89-99.
Orzechowski, M., X. E. Li, S. Fischer, & W. Lehman (2014) An atomic model of the tropomyosin cable on F-actin. Biophys. J. 107:694-699.
Gu C., J. Chang, V. A. Shchedrina, V. A. Pham, J. H. Hartwig, W. Suphamungmee, W. Lehman, B. T. Hyman, B. J. Bacskai, & S. Sever (2014) Regulation of dynamin oligomerization in cells: the role of dynamin-actin interactions and its GTPase activity. Traffic 15:819-838.
Li, X.E., M. Orzechowski, W. Lehman, & S. Fischer (2014) Structure and flexibility of the tropomyosin overlap junction. Biochem. Biophys. Res. Commun. 446:304-308.
Yang, S., L. Barbu-Tudoran, M. Orzechowski, R. Craig, J. Trinick, H. White & W. Lehman (2014) Three-dimensional organization of troponin on cardiac muscle thin filaments in the relaxed state. Biophys. J. 106:855-64.
Orzechowski, M., J. R. Moore, S. Fischer, W. Lehman (2014) Tropomyosin movement on F-actin during muscle activation explained analyzed by energy landscape determination. Arch. Biochem. Biophys. 2014 Mar 1;545:63-8.
Marston, S., M. Memo, A. Messer, M. Papadaki, K. Nowak, E. McNamara, R. Ong , M. EL-Mezgueldi, X. Li, & W. Lehman (2013) Mutations in repeating structural motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients. Human Mol. Genetics Dec 15;22(24):4978-87.
Lehman, W., X. E. Li, M. Orzechowski, & S. Fischer (2014) The structural dynamics of a-tropomyosin on F-actin shape the overlap complex between adjacent tropomyosin molecules. Arch. Biochem. Biophys. Jun 15;552-553:68-73.
We collaborate with colleagues in several laboratories with similar interests including:
Dr. Stuart Campbell, School of Engineering and Applied Science, Yale University.
Dr. Anthony Cammarato, Department of Medicine, Johns Hopkins University.
Dr. Roger Craig, Department of Cell Biology, University of Massachusetts Medical School.
Dr. Roberto Dominguez, Department of Physiology, University of Pennsylvania School of Medicine.
Dr. Stefan Fischer, Computational Biochemistry Group, University of Heidelberg, Heidelberg, Germany.
Dr. Michael Geeves, School of BioSciences, University of Kent, Canterbury, UK.
Dr. Peter Gunning, School of Medical Sciences, University of New South Wales, Sydney, Australia.
Dr. Steven B. Marston, National Heart and Lung Institute, Imperial College, London, UK.
Dr. Kathleen Morgan, Department of Health Sciences, Sargent College, Boston University.
Dr. Jeffrey Moore, Department of Biological Sciences, University of Massachusetts-Lowell.
Dr. Larry Tobacman, Departments of Biochemistry and Medicine, University of Illinois at Chicago.
William J. Lehman
Department of Physiology & Biophysics
Boston University School of Medicine
700 Albany Street, W408E
Boston MA 02118-2526