William J. Lehman, Ph.D.

William J. Lehman, Ph.D.

Professor of Physiology and Biophysics

B.S. State University of New York at Stony Brook
Ph.D. Princeton University

Phone: (617) 638-4397
Fax: (617) 638-4273
E-mail: wlehman@bu.edu
Address: see below
Link to BU Faculty Profile
Link to ORCID


Research

Fig1

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

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.

Reconstruction of troponin-tropomyosin regulated thin filaments, with the crystal structure of troponin fitted into its component density. From Yang et al., 2014.

Reconstruction of troponin-tropomyosin regulated thin filaments, with the crystal structure of troponin fitted into its component density. From Yang et al., 2014.

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.

 

Reconstruction of troponin-tropomyosin regulated thin filaments, with the crystal structure of troponin fitted into its component density. From Yang et al., 2014.

Cartoon representations of the movement of tropomyosin under the influence of troponin and Ca2+. Low Ca2+ – left, High Ca2+ – right, supported by our EM work and biochemical and physiological data of others.

Fig4Our 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 nonmuscle cells.

Fig5

Schematic of our general approach


Fig6The 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.


Recent Publications:

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.

Viswanathan, M. C., G. Kaushik, A. J. Engler, W. Lehman, & A. Cammarato (2013) A Drosophila melanogaster model of diastolic dysfunction and cardiomyopathy based on impaired troponin-T function. Circ. Res. Jan 17;114(2):e6-17.

Lehman, W, Orzechowski M, Li XE, Fischer S, Raunser S. Gestalt-binding of tropomyosin on actin during thin filament activation. J Muscle Res Cell Motility 2013 Aug; 34(3-4):155-63.

Janco, M, Lehrer SS, Suphamungmee W, Li XE, Lehman W, Geeves MA. Polymorphism in tropomyosin structure and function. J Muscle Res Cell Motility 2013 Aug;34(3-4):177-87.

Suphamungmee W, Nakamura F, Hartwig JH, Lehman W. Electron microscopy and 3D reconstruction reveals filamin Ig-domain binding to F-actin. J Mol Biol. 2012 Dec 14; 424(5):248-256.

Li XE, Suphamungmee W, Janco M, Geeves MA, Marston SB, Fischer S, Lehman W. The flexibility of two tropomyosin mutants, D175N and E180G, that cause hypertrophic cardiomyopathy. Biochem Biophys Res Commun. 2012 Aug 3;424(3):493-6. PubMed Central PMCID: PMC3412897.

Moore JR, Li X, Nirody J, Fischer S, Lehman W. Structural implications of conserved aspartate residues located in tropomyosin’s coiled-coil core. Bioarchitecture. 2011 Sep 1;1(5):250-255. PubMed PMID: 22754618; PubMed Central PMCID: PMC3384579.

Lehman W, Morgan KG. Structure and dynamics of the actin-based smooth muscle contractile and cytoskeletal apparatus. J Muscle Res Cell Motil. 2012 Feb 7, 33(6):461-469 PubMed Central PMCID: PMC3394904.

Jensen MH, Watt J, Hodgkinson JL, Gallant C, Appel S, El-Mezgueldi M, Angelini TE, Morgan KG, Lehman W, Moore JR. Effects of basic calponin on the flexural mechanics and stability of F-actin. Cytoskeleton (Hoboken). 2012 Jan;69(1):49-58. doi: 10.1002/cm.20548. Epub 2011 Dec 7. PubMed PMID: 22135101; PubMed Central PMCID: PMC3355516.

Rao JN, Rivera-Santiago R, Li XE, Lehman W, Dominguez R. Structural analysisof smooth muscle tropomyosin α and β isoforms. J Biol Chem. 2012 Jan 27;287(5):3165-74. Epub 2011 Nov 27. PubMed PMID: 22119916; PubMed Central PMCID: PMC3270971.

Cammarato A, Li XE, Reedy MC, Lee CF, Lehman W, Bernstein SI. Structural basismfor myopathic defects engendered by alterations in the myosin rod. J Mol Biol. 2011 Dec 9;414(4):477-84. Epub 2011 Oct 20. PubMed PMID: 22037585; PubMed Central PMCID: PMC3230674.

Collins A, Huang R, Jensen MH, Moore JR, Lehman W, Wang CL. Structural studies on maturing actin filaments. Bioarchitecture. 2011 May;1(3):127-133. PubMed PMID: 21922043; PubMed Central PMCID: PMC3173961.

East DA, Sousa D, Martin SR, Edwards TA, Lehman W, Mulvihill DP. Altering the stability of the Cdc8 overlap region modulates the ability of this tropomyosin to bind co-operatively to actin and regulate myosin. Biochem J. 2011 Sep1;438(2):265-73. PubMed PMID: 21658004.

Mun JY, Gulick J, Robbins J, Woodhead J, Lehman W, Craig R. Electron microscopy and 3D reconstruction of F-actin decorated with cardiac myosin-binding protein C (cMyBP-C). J Mol Biol. 2011 Jul 8;410(2):214-25. Epub 2011 May 13. PubMed PMID: 21601575; PubMed Central PMCID: PMC3115431.

Li XE, Tobacman LS, Mun JY, Craig R, Fischer S, Lehman W. Tropomyosin position on F-actin revealed by EM reconstruction and computational chemistry. Biophys J. 2011 Feb 16;100(4):1005-13. PubMed PMID: 21320445; PubMed Central PMCID: PMC3037716.

Gallant C, Appel S, Graceffa P, Leavis P, Lin JJ, Gunning PW, Schevzov G, Chaponnier C, DeGnore J, Lehman W, Morgan KG. Tropomyosin variants describe distinct functional subcellular domains in differentiated vascular smooth muscle cells. Am J Physiol Cell Physiol. 2011 Jun;300(6):C1356-65. Epub 2011 Feb 2. PubMed PMID: 21289288; PubMed Central PMCID: PMC3118631.

Coulton AT, East DA, Galinska-Rakoczy A, Lehman W, Mulvihill DP. The recruitment of acetylated and unacetylated tropomyosin to distinct actin polymers permits the discrete regulation of specific myosins in fission yeast. J Cell Sci. 2010 Oct 1;123(Pt 19):3235-43. Epub 2010 Aug 31. PubMed PMID: 20807799; PubMed Central PMCID: PMC2939800.

Sousa D, Cammarato A, Jang K, Graceffa P, Tobacman LS, Li XE, Lehman W. Electron microscopy and persistence length analysis of semi-rigid smooth muscle tropomyosin strands. Biophys J. 2010 Aug 4;99(3):862-8. PubMed PMID: 20682264; PubMed Central PMCID: PMC2913205.

Li XE, Lehman W, Fischer S. The relationship between curvature, flexibility and persistence length in the tropomyosin coiled-coil. J Struct Biol. 2010 May;170(2):313-8.

Galińska A, Hatch V, Craig R, Murphy AM, Van Eyk JE, Wang CL, Lehman W, Foster DB. The C terminus of cardiac troponin I stabilizes the Ca2+-activated state of tropomyosin on actin filaments. Circ Res. 2010 Mar 5;106(4):705-11. Epub 2009 Dec 24. PubMed PMID: 20035081; PMCID: PMC2834238.

Li XE, Lehman W, Fischer S, Holmes KC. Curvature variation along the tropomyosin molecule. J Struct Biol. 2010 May;170(2):307-12. Epub 2009 Dec 22. PubMed PMID: 20026408; PMCID: PMC2856783.

Cammarato A, Craig R, Lehman W. Electron microscopy and three-dimensional reconstruction of native thin filaments reveal species-specific differences inregulatory strand densities. Biochem Biophys Res Commun. 2010 Jan 1;391(1):193-7 Epub 2009 Nov 10. PMCID: PMC2818542.

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

Dr. Steven B. Marston, Nationall 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 MassachusettsLowell.

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

Dr. Stefan Raunser, Max Planck Inst of Molecular Physiology, Dortmund, Germany.

Contact Us

William J. Lehman
Department of Physiology and Biophysics
Boston University School of Medicine
700 Albany Street, W408E
Boston MA 02118-2526

Phone:(617) 638-4397
Fax: (617) 638-4273

e-mail: wlehman@bu.edu

Directory|BUMC
May 3, 2017
Primary teaching affiliate
of BU School of Medicine