Dr. Larry Tobacman

Larry Tobacman, MD
Director, Medical Scientist Training Program
Senior Associate Dean for Research
Professor of Medicine and Physiology and Biophysics
140 CMW, MC 784
Phone 312-413-9688
Fax 312-996-9006
Email LST@uic.edu

Regulation of cardiac and skeletal muscle contraction by troponin and tropomyosin

Each heartbeat and 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
Li, X.E., L. S. Tobacman, J. Y. Mun, R. Craig, S. Fisher, and W. Lehman. (2011) Tropomyosin Position on F-Actin Revealed by EM Reconstruction and Computational Chemistry. Biophys. J. 100 (In Press)
Ali, L., Cohen, J.M., and Tobacman, L.S. (2010) Push and Pull of Tropomyosin’s Opposite Effects on Myosin Attachment to Actin. A Chimeric Tropomyosin Host-Guest Study. Biochemistry 49: 10873-10880.
Kowlessur, D. and Tobacman, L. S. (2010) Low Temperature Dynamic Mapping Reveals Unexpected Order and Disorder in Troponin. J. Biol. Chem. 285: 38978-38986.
Kozaili, J.M., Leek, D., and Tobacman, L.S. (2010) Dual Regulatory Functions of the Thin Filament Revealed by Replacement of the Troponin I Inhibitory Peptide with a Linker. J. Biol. Chem. 285: 38034-38041.
Kowlessur, D. and Tobacman, L. S. (2010) Troponin Regulatory Function and Dynamics Revealed by H/D Exchange-Mass Spectrometry. J. Biol. Chem. 285: 2686-2694.
Sousa,D., Cammarato,A., Jang,K., Graceffa,P., Tobacman,L.S., Li,X.E., Lehman,W. (2010) Electron Microscopy and Persistence Length Analysis of Semi-Rigid Smooth Muscle Tropomyosin Strands. Biophys. J. 99: 862-868.
Sithanandan, V., Tobacman, L.S., Van Gorder, N., and Homsher, E. (2009) Mechanical and Kinetic Effects of Shortened Tropomyosin Reconstituted into Myofibrils. Pflügers Archiv-European Journal of Physiology 458: 761-76.
Galinska-Rakoczy, A., Engel, P., Xu, C., Jung, H., Craig, R., Tobacman, L.S., Lehman, W. (2008) Structural Basis for the Regulation of Muscle Contraction by Troponin and Tropomyosin. J. Mol. Biol. 379: 929–935.
Pirani,A., Vinogradova,M.V., Curmi,P.M.G., King,W.A., Fletterick,R.J., Craig,R., Tobacman,L., Xu,C., Hatch,V., and Lehman,W. (2006). An Atomic Model of the Thin Filament in the Relaxed and Ca2+-Activated States. J.Mol.Biol., 357 707-717.
Lu, X. Tobacman, L.S., and Kawai, M. (2006) Temperature-dependence of isometric tension and cross-bridge kinetics of cardiac muscle fibers reconstituted with a tropomyosin internal deletion mutant. Biophys. J. 91: 4230-4240.
Pirani, A., Xu, C., Hatch, V. Craig, R. Tobacman, L.S., and Lehman, W. (2005) Single Particle Analysis of Relaxed and Activated Muscle Thin Filaments. J. Mol. Biol., 346: 761-772.
Gong, H., Hatch. V., Ali L., Lehman, Craig, R. and Tobacman, L.S. (2005): Mini-Thin Filaments Regulated by Troponin-Tropomyosin. Proc. Natl. Acad. Sci., USA 102: 656-661.
Brown,J.H., Zhou,Z., Reshetnikova,L., Robinson,H., Yammani.R.A., Tobacman,L.S., and Cohen,C. (2005). Structure of Tropomyosin's Mid-Region: Bending and Binding Sites for Actin. Proc.Natl.Acad.Sci., USA, 102:18878-83.

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

Homsher, E., Nili, M., Chen, I., and Tobacman, L.S. (2003) Regulatory Proteins Alter Nucleotide Binding to Acto-Myosin of Sliding Filaments in Motility Assays. Biophys. J., 85: 1046-1052.

Hinkle, A., and Tobacman, L.S. (2003) Folding and Function of the Troponin Tail Domain: Effects of Cardiomyopathic Troponin T Mutations. J. Biol. Chem. 278: 506-513.

Morris, C.A., Tobacman, L.S., and Homsher, E. (2003) Thin Filament Activation and Unloaded Shortening Velocity of Rabbit Skinned Muscle Fibres. J. Physiol. (Lond.), 550: 205-215.

Piroddi, N., Tesi, C., Pellegrino, M.A., Tobacman, L.S., Homsher, E., and Poggesi, C. (2003) Contractile Effects of the Exchange of Cardiac Troponin for Fast Skeletal Troponin in Rabbit Psoas Single Myofibrils. J. Physiol. (Lond.), 552: 917-931.

Pavlov, D., Gerson, J.H.., Yu, T., Tobacman, L.S., Homsher, E., and Reisler, E. (2003) The Regulation of Subtilisin Cleaved Actin by Tropomyosin/Troponin. J. Biol. Chem. 278: 5517-5522.

Lu, X., Tobacman, L.S., and Kawai, M. (2003) Effects of Tropomyosin Internal Deletion Delta23 on Isometric Tension and the Cross-Bridge Kinetics in Bovine Myocardium. J. Physiol. (Lond.) 553: 457-471. 

Heller, M., Tobacman, L.S., Nili, M., and Homsher, E. (2003)  Cardiomyopathy Mutations that Increase Calcium-sensitivity and Tropomyosin N-Domain Flexibility. J. Biol. Chem. 278: 41742-41748.

Tobacman, L. S. (2002) 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.

Tobacman, L.S., Nili, M., Butters, C., Heller, V., Craig, R., Lehman, W., and Homsher, E. (2002) The Troponin Tail Domain Promotes a Conformational State of the Thin Filament That Suppresses Myosin Activity. J. Biol. Chem., 277: 27636-27642.

Li, Y., Mui, S., Brown, J.H., Strand, J., Reshetnikova, L., Tobacman, L.S., and Cohen, C. (2002) 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.

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. (2001) Hypertrophic Cardiomyopathy Caused by a Novel α-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.

Burhop, J., Rosol, M., Craig, R., Tobacman, L.S., and Lehman, W. (2001) Effects of a Cardiomyopathy-Causing Troponin T Mutation on Thin Filament Function and Structure. J. Biol. Chem., 276: 20788-20794.

Morris, C.A., Tobacman, L.S., and Homsher, E. (2001) Modulation of Contractile Activation in Skeletal Muscle by a Calcium-insensitive Troponin C Mutant. J. Biol. Chem., 276: 20245-20251.

Lehman, W., Rosol, M., Tobacman, L.S., and Craig, R. (2001) Troponin Organization on Relaxed and Activated Thin Filaments Revealed by Electron Microscopy and Three-dimensional Reconstruction. J. Mol. Biol. 307: 739-744.

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. and Butters, C.A. (2000) A New Model of Cooperative Myosin-Thin Filament Binding. J. Biol. Chem. 275: 27587-27593.

Rosol, M., Lehman, R., Craig, R., Landis, C., and Tobacman, L.S. (2000) Three-Dimensional Reconstruction of Thin Filaments Containing Mutant Tropomyosin. Biophys. J. 78: 908-917.

Homsher, E., Lee, D.M., Morris, C., Pavlov, D. and Tobacman, L.S. (2000)  Regulation of Force and Unloaded Sliding Speed in Single Thin Filaments: Effects of Regulatory Proteins and Calcium. J. Physiol. (Lond) 524: 233-243.

Korman, V.L., Hatch, V., Dixon, K., Craig, R., Lehman, W., and Tobacman, L.S.: An Actin Subdomain 2 (2000) Mutation that Impairs Thin Filament Regulation by Troponin and Tropomyosin. J. Biol. Chem. 275: 22470-22478.

Lehman, W., Hatch, T., Korman, V., Rosol, M., Thomas, L.T., Maytum, R., Geeves, M., Van Eyk, J., Tobacman, L.S., and Craig, R. (2000) Tropomyosin and Actin Isoforms Modulate the Localization of Tropomyosin Strands on Actin Filaments. J. Mol. Biol. 302: 593-606.