William J. Lehman, Ph.D.

Atomic model showing tropomyosin moving between three positions on actin. Red - Blocked; Yellow - Ca2+-activated; Green - Myosin-activated. From Poole et al., 2006.

Research

We are involved in structural studies on the assembly and function of actin-containing thin filaments in muscle and non-muscle cells. Our principal goal is to analyze and elucidate the mechanisms of thin filament-linked regulation of muscle contraction. To accomplish this goal, we use a combination of molecular biology, electron microscopy, electron tomography, image reconstruction and molecular dynamics protocols to better understand the interactions and dynamics of protein components of isolated and reconstituted thin filaments. Studies on mutants are carried out to better understand abnormal filament function in disease processes.  

Reconstruction of troponin-tropomyosin regulated thin filaments, with the crystal structure of troponin fitted into its component density. From Pirani et al., 2006.

Our laboratory confirmed 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 have 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.  

Our laboratory is continuing the above-mentioned studies to obtain even greater resolution of the processes involved. 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 are also engaged in studies on the structural interactions of other actin binding proteins including α-actinin, caldesmon, calponin, cortactin, and native and mutant dystrophin, namely proteins that play important roles in the organization of the cytoskeleton in striated and smooth muscles as well as in non-muscle cells.

Cartoon representations of the movement of tropomyosin under the influence of troponin and Ca2+. Low Ca2+ - left, High Ca2+ - right. From Galińska-Rakoczy et al., 2008 and Lehman et al., 2009. Graphics by Moore Design.

Recent Publications:

Pirani, A., M. V. Vinogradova, P. M. G. Curmi, W. A. King, R. J. Fletterick, R. Craig, L. S. Tobacman, C. Xu, V. Hatch,  & W. Lehman (2006) An atomic model of the thin filament in the relaxed and Ca²⁺-activated states J. Mol. Biol. 357: 707-717. doi:10.1016/j.jmb.2005.12.050 

Pant, K., D. Chereau, V. Hatch, R. Dominguez & W. Lehman (2006) Cortactin binding to F-actin revealed by electron microscopy and 3D reconstruction.  J. Mol. Biol. 359, 840-847. doi:10.1016/j.jmb.2006.03.065 

Poole, K. J., M. Lorenz, G. Evans, G. Rosenbaum, A. Pirani, L. S. Tobacman, W. Lehman & K.C. Holmes (2006) A comparison of muscle thin filament models obtained from electron microscopy reconstructions and low-angle X-ray fibre diagrams from non-overlap muscle. J. Struct. Biol. 155, 273-284. doi:10.1016/j.jsb.2006.02.020 

Skoumpla, K., A. T. Coulton, W. Lehman, M. A. Geeves & D. P. Mulvihill. (2007) Acetylation regulates tropomyosin function in the fission yeast Schizosaccharomyces pombe. J. Cell Sci. 120, 1635-1645. doi: 10.1242/10.1242/jcs.001115

Greenberg, M. J., C.-L. Wang, W. Lehman & J. R. Moore (2008) Modulation of actin mechanics by caldesmon and tropomyosin. Cell Motil. Cytoskeleton 65, 156-164. doi:10.1002/cm.20251 

Lehman, W. & Craig, R. (2008) Tropomyosin and the Steric Mechanism of Muscle Regulation. Adv. Exp. Med. Biol. 644, 95-109. Review.

Maytum, R., M. Konrad, V. Hatch, W. Lehman & M. A. Geeves.  (2008) Ultra short yeast tropomyosins show novel myosin regulation.  J. Biol. Chem. 283, 1902-1910. doi:10.1074/jbc.M708593200

Galińska-Rakoczy, A., P. Engel, C. Xu, H.-S. Jung, R. Craig, L.S. Tobacman & W. Lehman. (2008) Structural basis for the regulation of muscle contraction by troponin and tropomyosin. J. Mol. Biol. 379, 929-935. doi:10.1016/j.jmb.2008.04.062  

Holmes, K. C. & W. Lehman. (2009) Gestalt-binding of tropomyosin to actin filaments. J. Muscle Research Cell Motility 29, 213-219. doi: 10.1007/s10974-008-9157-6

Lehman, W., A. Galińska-Rakoczy, V. Hatch, L. S. Tobacman & R. Craig. (2009) Structural basis for the activation of muscle contraction by troponin and tropomyosin. J. Mol. Biol. 388, 673-681, doi:10.1016/j.jmb.2009.03.060 

Collaborations

We collaborate closely with several laboratories with similar interests including:

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. Kenneth C. Holmes, Max Planck Institut fϋr Medizinische Forschung, Heidelberg (Germany).

Dr. Kathleen Morgan, Department of Health Sciences, Sargent College, Boston University.

Dr. Jeffrey Moore, Department of Physiology & Biophysics, Boston University School of Medicine.

Dr. Dan Mulvihill, Department of Biosciences, University of Kent, Canterbury, UK.

Dr. Larry Tobacman, Departments of Biochemistry and Internal Medicine, University of Iowa College of Medicine.

Dr. Albert Wang, Department of Muscle Research, Boston Biomedical Research Institute

Positions Available

Senior Electron Microscopy Technician
&
Postdoctoral Fellow

 A Postdoctoral Research Fellow and a Senior Electron Microscopy Technician are sought to carry out research work on the structure of actin filament complexes that (1) are associated with cardiac and skeletal muscle regulatory proteins to control muscle activity and (2) interact with smooth muscle actin-binding proteins to modulate the assembly of the smooth muscle cytoskeleton. Applicants must have several years of experience in high-resolution EM work and first-rate facility with computer-assisted image analysis. Prior familiarity with preserving and recording macromolecular assemblies in negative stain and by cryo-EM methods would be invaluable. Experience in supervising graduate students and postdoctoral fellows would also be important.

 Interested applicants should send their CV with three references to:
Dr. William Lehman
Professor of Physiology & Biophysics
Department of Physiology & Biophysics
Boston University School of Medicine
72 East Concord Street
Boston, MA 02118

Or email: wlehman@bu.edu

Contact Us

William J. Lehman
Department of Physiology and Biophysics
Boston University School of Medicine
72 East Concord Street
Boston MA 02118-2526

Phone:(617) 638-4397
Fax: (617) 638-4273
e-mail: wlehman@bu.edu