Larry Tobacman, M.D.
Professor of Medicine and Physiology and Biophysics
Director, MD-PhD Program
Regulation of cardiac and skeletal muscle contraction by troponin and tropomyosin
Each heartbeat, each finger-strike of a computer key is directly controlled where myosin binds to actin: on troponin-tropomyosin regulated thin filaments. The Tobacman laboratory investigates this regulation by multi-disciplinary examination of the thin filament, in solution and in the sarcomere, applying both functional and structural approaches. Cooperative activation of muscle contraction is attributable to transitions among thin filament quaternary structures, and to the effects of ligands (calcium, myosin) on these transitions. By experiment and by calculation, using biophysics, biochemistry, molecular biology, and structural biology, we seek mechanistic insights into these phenomena. Additionally, contractile protein mutations that cause inherited heart disease are under investigation. Depending upon the mutation, affected kindreds experience dilated cardiomyopathy, hypertrophic cardiomyopathy, or mild hypertrophy with a high risk of sudden death. We study cardiomyopathic thin filament proteins, both to understand basic aspects of disease pathogenesis, and also as tools to investigate the structure and function of these molecules.
Recent Publications
Xu, C., Craig, R., Tobacman, L., Horowitz, R., and Lehman, W.: Tropomyosin Positions in Regulated Thin Filaments Revealed by Cryo-Electron Microscopy. Biophys. J. 77: 985-992, 1999.
Hinkle, A., Goranson, A., Butters, C.A., and Tobacman, L.S.: Roles for the Troponin Tail Domain in Thin Filament Assembly and Regulation. A Deletional Study of Cardiac Troponin T. J. Biol. Chem. 274: 7157-7164, 1999.
Korman, V.L., and Tobacman, L.S.: Mutations in Actin Subdomain 3 that Impair Thin Filament Regulation by Troponin and Tropomyosin J. Biol. Chem. 274: 22191-22196 1999.
Tobacman, L.S., Lin, D., Butters, C., Landis, C., Back, N., and Homsher, E.: Functional Consequences of Troponin T Mutations Found in Hypertrophic Cardiomyopathy. J. Biol. Chem. 274: 28363-28370, 1999.
Landis, C., Back, N., Homsher, E., and Tobacman, L.S. Effects of Tropomyosin Internal Deletions on Thin Filament Function. J. Biol. Chem. 274: 31279-31285, 1999.
Rosol, M., Lehman, R., Craig, R., Landis, C., and Tobacman, L.S.: Three-Dimensional Reconstruction of Thin Filaments Containing Mutant Tropomyosin. Biophys. J. 78: 908-917, 2000.
Homsher, E., Lee, D.M., Morris, C., Pavlov, D. and Tobacman, L.S.: Regulation of Force and Unloaded Sliding Speed in Single Thin Filaments: Effects of Regulatory Proteins and Calcium. J. Physiol. (Lond) 524: 233-243, 2000.
Korman, V.L., Hatch, V., Dixon, K., Craig, R., Lehman, W., and Tobacman, L.S.: An Actin Subdomain 2 Mutation that Impairs Thin Filament Regulation by Troponin and Tropomyosin. J. Biol. Chem. 275: 22470-22478, 2000.
Lehman, W., Hatch, T., Korman, V., Rosol, M., Thomas, L.T., Maytum, R., Geeves, M., Van Eyk, J., Tobacman, L.S., and Craig, R. Tropomyosin and Actin Isoforms Modulate the Localization of Tropomyosin Strands on Actin Filaments. J. Mol. Biol. 302: 593-606, 2000.
Tobacman, L.S. and Butters, C.A.: A New Model of Cooperative Myosin-Thin Filament Binding. J. Biol. Chem. 275: 27587-27593, 2000.
Karibe,A., Tobacman, L.S., Strand, J., Butters, C., Back, N., Bachinski, L.L., Arai, A.E., Ortiz, A., Roberts, R., Homsher, E., Fananapazir, L.Hypertrophic Cardiomyopathy Caused by a Novel ?-Tropomyosin Mutation (V95A) Is Associated with Mild Cardiac Phenotype, Abnormal Calcium Binding to Troponin and Myosin Cycling, and a Poor Prognosis. Circulation 103: 65-71, 2001.
Burhop, J., Rosol, M., Craig, R., Tobacman, L.S., and Lehman, W.: Effects of a Cardiomyopathy-Causing Troponin T Mutation on Thin Filament Function and Structure. J. Biol. Chem., 276: 20788-20794, 2001.
Morris, C.A., Tobacman, L.S., and Homsher, E.: Modulation of Contractile Activation in Skeletal Muscle by a Calcium-insensitive Troponin C Mutant. J. Biol. Chem., 276: 20245-20251, 2001.
William Lehman, W., Rosol, M., Tobacman, L.S., and Craig, R. Troponin Organization on Relaxed and Activated Thin Filaments Revealed by Electron Microscopy and Three-dimensional Reconstruction. J. Mol. Biol. 307: 739-744, 2001.
Strand, J., Nili, M. Homsher, E. and Tobacman, L.S.: Modulation of Myosin Function by Isoform-Specific Properties of S. Cerevisiae and Muscle Tropomyosins. J. Biol. Chem., 276: 34832-34839, 2001.
Tobacman, L. S.: Structure and Regulation of Cardiac and Skeletal Muscle Thin Filaments, In: Molecular Control Mechanisms in Striated Muscle Contraction, J.R. Solaro & R. L. Moss, Eds., Kluwer Academic Publishers, 2002.
Tobacman, L.S., Nili, M., Butters, C., Heller, V., Craig, R., Lehman, W., and Homsher, E.: The Troponin Tail Domain Promotes a Conformational State of the Thin Filament That Suppresses Myosin Activity. J. Biol Chem., 277: 27636-27642, 2002.
Li, Y., Mui, S., Brown, J.H., Strand, J., Reshetnikova, L., Tobacman, L.S., and Cohen, C.: The Crystal Structure of the C-terminal Fragment of Striated Muscle -Tropomyosin Reveals a Key Troponin T Recognition Site. Proc. Natl. Acad. Sci., USA, 99: 7378-7383, 2002.
Homsher, E., Nili, M., Chen, I., and Tobacman, L.S.: Regulatory Proteins Alter Nucleotide Binding to Acto-Myosin of Sliding Filaments in Motility Assays. Biophys. J., 85: 1046-1052, 2003.
Hinkle, A., and Tobacman, L.S.: Folding and Function of the Troponin Tail Domain: Effects of Cardiomyopathic Troponin T Mutations. J. Biol. Chem. 278: 506-513, 2003.
Morris, C.A., Tobacman, L.S., and Homsher, E.: Thin Filament Activation and Unloaded Shortening Velocity of Rabbit Skinned Muscle Fibres. J. Physiol. (Lond.), 550: 205-215, 2003.
Piroddi, N., Tesi, C., Pellegrino, M.A., Tobacman, L.S., Homsher, E., and Poggesi, C.: Contractile Effects of the Exchange of Cardiac Troponin for Fast Skeletal Troponin in Rabbit Psoas Single Myofibrils. J. Physiol. (Lond.), 552: 917-931, 2003.
Pavlov, D., Gerson, J.H.., Yu, T., Tobacman, L.S., Homsher, E., and Reisler, E.: The Regulation of Subtilisin Cleaved Actin by Tropomyosin/Troponin. J. Biol. Chem. 278: 5517-5522, 2003.
Lu, X., Tobacman, L.S., and Kawai, M.: Effects of Tropomyosin Internal Deletions on Isometric Tension and the Cross-Bridge Kinetics in Bovine Myocardium. J. Physiol. (Lond.), 2003. (In Press)
Heller, M., Tobacman, L.S., and Homsher, E.: Cardiomyopathic Tropomyosin Mutations that Increase Thin Filament Ca2+-Sensitivity and Tropomyosin N-Domain Flexibility. J. Biol. Chem. 278: 41742-41748, 2003.
Cammarato, A., Hatch, V., Saide, J., Craig, R., Sparrow, J., Tobacman, L.S.
and Lehman, W.: Drosophila Muscle Regulation Characterized by Electron Microscopy
and 3D Reconstruction of Thin Filament Mutants. Biophysical Journal, 2004 (In
Press)