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 and image reconstruction 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 and in non-muscle cells.

Recent Publications:

Cammarato, A., V. Hatch, J. Saide, R. Craig, J. C. Sparrow, L. S. Tobacman, & W. Lehman (2004) Drosophila Muscle Regulation Characterized by Electron Microscopy and 3D Reconstruction of Thin Filament Mutants. Biophys. J. 86:1618-1624.    

Foster, D.B., R. Huang, V. Hatch, R. Craig, P. Graceffa, W. Lehman,  & C.L. Wang (2004) Modes of Caldesmon Binding to Actin: Sites of Caldesmon Contact and Modulation of Interactions by Phosphorylation. J. Biol. Chem. 279: 53387-53394.

Lehman, W., R. Craig, J. Kendrick-Jones, & A. J. Sutherland-Smith (2004) An 0pen or Closed Case for the Conformation of Calponin Homology Domains on F-actin? J. Muscle Research Cell Motility 25: 351-358.      

Lehman, W. & R. Craig (2004) The Structure of the Vertebrate Striated Muscle Thin Filament: a Tribute to the Contributions of Jean Hanson. J. Muscle Research Cell Motility 25: 455-466.

Pirani, A., C. Xu, V. Hatch, R. Craig, L.S. Tobacman & W. Lehman (2005) Single Particle Analysis of Relaxed and Activated Muscle Thin Filaments. J. Mol. Biol. 346: 761-772.

Cammarato, A., R. Craig, J.C. Sparrow & W. Lehman (2005) A Charge Reversal on Actin Perturbs Steric Regulation of Thin Filaments. J. Mol. Biol. 347: 889-894.

Gong, H., Hatch, V, Ali, L., Lehman, W., Craig, R. & L. S. Tobacman (2005) Mini-thin Filaments Regulated by Troponin-Tropomyosin. Proc. Natl. Acad. Sci. (USA) 102: 656-661.

Pirani, A. Vinogradova, M.V., Curmi, P.M.G, King, W.A. Fletterick, R.J., Craig, R. Tobacman, L.S., Xu, C., Hatch, V. & W. Lehman (2006) An Atomic Model of the Thin Filament in the Relaxed and Ca²⁺-Activated states. J. Mol. Biol. 357:707-717.

Pant, K., Chereau, D., Hatch, V., Dominguez, R., & W. Lehman (2006) Cortactin Binding to F-Actin Revealed by Electron Microscopy and 3D Reconstruction. J. Mol. Biol. 359:840-847.

Poole, K.J.V., Lorenz, M., Evans, G., Rosenbaum, G., Pirani, A., Craig, R., Tobacman, L.S., Lehman, W., & Holmes, K.C. (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. (in press).

Collaborations

We collaborate closely with several laboratories with similar interests including:

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

Dr. Roger Craig, Department of Cell Biology, University of Massachusetts Medical School.

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

Dr. Roberto Dominguez, Department of Physiology, University of Pennsylvania School of Medicine.

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

Dr. Andrew Sutherland-Smith, Institute of Molecular BioSciences, Massey University (New Zealand).

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

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
715 Albany Street
Boston, MA 02118

Or email: wlehman@bu.edu

Contact Us

William J. Lehman
Department of Physiology and Biophysics
Boston University School of Medicine
715 Albany Street
Boston MA 02118-2526

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