William J. Lehman, PhD
Professor
Boston University School of Medicine
Dept of Physiology & Biophysics

PhD, Princeton University



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 and cytoskeletal remodeling. 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. We have an excellent track record in successfully educating graduate and post-doctoral students in the application of the state-of-the-art techniques that we use. In particular, we have trained students with backgrounds in biological and biochemical sciences (my own experience) to be fearless about the challenge of carrying out sophisticated biophysical approaches, and, conversely, teaching students with background in physical and computational sciences to understand the biomedical underpinnings of our work. This dual process of training students with these diverse backgrounds in one laboratory setting is synergistic. As a sign of our success, of the 19 papers that have been published by us since 2007, 12 were co-authored by 5 different post-doctoral fellows and by 3 graduate students from my laboratory.
Our laboratory was the first to directly visualize 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 during muscle activation tropomyosin moves away from myosin cross-bridge binding sites on actin in two highly cooperative 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 a-actinin, caldesmon, calponin, cortactin, filamin 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.

Graduate Faculty (Primary Mentor of Grad Students)
Boston University School of Medicine, Division of Graduate Medical Sciences



2011-2011 Hungarian Academy of Sciences & Eotvos Lorand University: Chosen to deliver first Albert Szent-Gyorgyi Lecture in Budapest, Hungary


Thin Filaments and Muscle Regulation
12/01/2015 - 11/30/2017 (PI)
NIH/National Heart, Lung, and Blood Institute
5R37HL036153-27

Structural Analysis of Anticancer Compound Targets on Tpm3.1 Tropomyosin
04/01/2016 - 06/30/2017 (PI)
Novogen

Cooperativity in Cardiac Myofilament Interactome in Health and Disease
08/11/2016 - 05/31/2017 (PI)
University of Massachusetts, Lowell NIH NHLBI
1R01HL123774-01A1

Thin Filaments and Muscle Regulation
12/07/2012 - 11/30/2015 (PI)
NIH/National Heart, Lung, and Blood Institute
5R37HL036153-25

Pathogenesis and In Vivo Suppression of Thin Filament Based Cardiomyopathies of Thin Filament Based Cardiomyopathies
01/01/2015 - 06/30/2015 (PI)
Johns Hopkins University NIH NHLBI
1R56HL124091-01

DYNAMICS OF THE VASCULAR SMOOTH MUSCLE CYTOSKELETON
07/01/2007 - 06/30/2014 (SP Co-PI of Sub-Project / SP)
PI: Kathleen Morgan, PhD
NIH/National Heart, Lung, and Blood Institute
5P01HL086655-05

Thin Filaments and Muscle Regulation
09/30/1986 - 11/30/2012 (PI)
NIH/National Heart, Lung, and Blood Institute
5R37HL036153-22

An Atomic Structure of Dystrophin Bound to F-Actin
01/01/2004 - 12/31/2006 (PI)
Muscular Dystrophy Association




Yr Title Project-Sub Proj Pubs
2017 Thin Filaments and Muscle Regulation 5R37HL036153-27 18
2016 Thin Filaments and Muscle Regulation 4R37HL036153-26 18
2015 Thin Filaments and Muscle Regulation 5R37HL036153-25 18
2014 Thin Filaments and Muscle Regulation 5R37HL036153-24 18
2013 Thin Filaments and Muscle Regulation 4R37HL036153-23 18
2012 Thin Filaments and Muscle Regulation 5R37HL036153-22 18
2011 Thin Filaments and Muscle Regulation 5R37HL036153-21 18
2011 Thin Filaments and Muscle Regulation 5R37HL036153-21 18
2011 Structure and Mechanics of Smooth Muscle Thin Filaments 5P01HL086655-05-3 61
2010 Thin Filaments and Muscle Regulation 5R37HL036153-20 18
Showing 10 of 34 results. Show All Results
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.

  1. Lehman W. Switching Muscles On and Off in Steps: The McKillop-Geeves Three-State Model of Muscle Regulation. Biophys J. 2017 Jun 20; 112(12):2459-2466. PMID: 28552313.
  2. Sewanan LR, Moore JR, Lehman W, Campbell SG. Predicting Effects of Tropomyosin Mutations on Cardiac Muscle Contraction through Myofilament Modeling. Front Physiol. 2016; 7:473.View Related Profiles. PMID: 27833562.
  3. Rynkiewicz MJ, Fischer S, Lehman W. The propensity for tropomyosin twisting in the presence and absence of F-actin. Arch Biochem Biophys. 2016 Nov 01; 609:51-58.View Related Profiles. PMID: 27663225; DOI: 10.1016/j.abb.2016.09.008;.
  4. Lehman W. Thin Filament Structure and the Steric Blocking Model. Compr Physiol. 2016 Mar 15; 6(2):1043-69. PMID: 27065174; DOI: 10.1002/cphy.c150030;.
  5. Moore JR, Campbell SG, Lehman W. Structural determinants of muscle thin filament cooperativity. Arch Biochem Biophys. 2016 Mar 15; 594:8-17.View Related Profiles. PMID: 26891592; PMCID: PMC4792785; DOI: 10.1016/j.abb.2016.02.016;.
  6. Fischer S, Rynkiewicz MJ, Moore JR, Lehman W. Tropomyosin diffusion over actin subunits facilitates thin filament assembly. Struct Dyn. 2016 Jan; 3(1):012002.View Related Profiles. PMID: 26798831; DOI: 10.1063/1.4940223;.
  7. Rynkiewicz MJ, Schott V, Orzechowski M, Lehman W, Fischer S. Electrostatic interaction map reveals a new binding position for tropomyosin on F-actin. J Muscle Res Cell Motil. 2015 Dec; 36(6):525-33.View Related Profiles. PMID: 26286845; PMCID: PMC4760918; DOI: 10.1007/s10974-015-9419-z;.
  8. Alamo L, Li XE, Espinoza-Fonseca LM, Pinto A, Thomas DD, Lehman W, Padrón R. Tarantula myosin free head regulatory light chain phosphorylation stiffens N-terminal extension, releasing it and blocking its docking back. Mol Biosyst. 2015 Aug; 11(8):2180-9.View Related Profiles. PMID: 26038302; PMCID: PMC4503497; DOI: 10.1039/c5mb00163c;.
  9. Schmidt WM, Lehman W, Moore JR. Direct observation of tropomyosin binding to actin filaments. Cytoskeleton (Hoboken). 2015 Jun; 72(6):292-303.View Related Profiles. PMID: 26033920; PMCID: PMC4529784; DOI: 10.1002/cm.21225;.
  10. Begonja AJ, Pluthero FG, Suphamungmee W, Giannini S, Christensen H, Leung R, Lo RW, Nakamura F, Lehman W, Plomann M, Hoffmeister KM, Kahr WH, Hartwig JH, Falet H. FlnA binding to PACSIN2 F-BAR domain regulates membrane tubulation in megakaryocytes and platelets. Blood. 2015 Jul 2; 126(1):80-8.View Related Profiles. PMID: 25838348; PMCID: PMC4492198; DOI: 10.1182/blood-2014-07-587600;.
Showing 10 of 116 results. Show More

This graph shows the total number of publications by year, by first, middle/unknown, or last author.

Bar chart showing 100 publications over 38 distinct years, with a maximum of 9 publications in 2011

YearPublications
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In addition to these self-described keywords below, a list of MeSH based concepts is available here.

actin
caldesmon
calponin
Electron Microscopy
Molecular Dynamics
muscle regulation
tropomyosin
troponin

Available to Mentor as: (Review Mentor Role Definitions):
  • Advisor
  • Project Mentor
  • Research / Scholarly Mentor
Contact for Mentoring:


72 E. Concord St Instructional (L)
Boston MA 02118
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