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, Graduate Medical Sciences



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


Revealing Pathomechanisms of Mutant TPM1 Through a Hybrid Computational-Experimental Approach
07/10/2017 - 06/30/2022 (Subcontract PI)
Yale University NIH NHLBI
5R01HL136590-03

Thin Filaments and Muscle Regulation
01/01/2018 - 12/31/2021 (PI)
NIH/National Heart, Lung, and Blood Institute
5R01HL036153-30

Cooperativity in Cardiac Myofilament Interactome in Health and Disease
08/11/2016 - 05/31/2020 (Subcontract PI)
University of Massachusetts, Lowell NIH NHLBI
5R01HL123774-02

X-Ray Crystallography of TPM3.1 N- and C-terminal peptides
12/01/2018 - 09/30/2019 (PI)
TroBio Therapeutics Pty Ltd


Targeting Tropomyosin as a Novel Anti-Cancer Therapy
12/01/2017 - 11/30/2018 (Subcontract PI)
Kazia Therapeutics Ltd Australian Cmlth Gov


Thin Filaments and Muscle Regulation
12/01/2015 - 12/31/2017 (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


Thin Filaments and Muscle Regulation
12/07/2012 - 11/30/2016 (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 (Subcontract 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

Showing 10 of 12 results. Show All Results


Title


Yr Title Project-Sub Proj Pubs
2020 Thin Filaments and Muscle Regulation 5R01HL036153-30 61
2019 Thin Filaments and Muscle Regulation 5R01HL036153-29 61
2019 Thin Filaments and Muscle Regulation 5R01HL036153-29 61
2018 Thin Filaments and Muscle Regulation 2R01HL036153-28 61
2017 Thin Filaments and Muscle Regulation 5R37HL036153-27 73
2016 Thin Filaments and Muscle Regulation 4R37HL036153-26 73
2015 Thin Filaments and Muscle Regulation 5R37HL036153-25 73
2014 Thin Filaments and Muscle Regulation 5R37HL036153-24 73
2013 Thin Filaments and Muscle Regulation 4R37HL036153-23 73
2012 Thin Filaments and Muscle Regulation 5R37HL036153-22 73
Showing 10 of 38 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.

iCite Analysis       Copy PMIDs To Clipboard

  1. Doran MH, Pavadai E, Rynkiewicz MJ, Walklate J, Bullitt E, Moore JR, Regnier M, Geeves MA, Lehman W. Cryo-EM and Molecular Docking Shows Myosin Loop 4 Contacts Actin and Tropomyosin on Thin Filaments. Biophys J. 2020 Aug 18; 119(4):821-830.View Related Profiles. PMID: 32730789
     
  2. Pavadai E, Lehman W, Rynkiewicz MJ. Protein-Protein Docking Reveals Dynamic Interactions of Tropomyosin on Actin Filaments. Biophys J. 2020 Jul 07; 119(1):75-86.View Related Profiles. PMID: 32521240
     
  3. Lehman W, Maéda Y. Introducing a special issue of the Journal of Muscle Research and Cell Motility on actin and actin-binding proteins. J Muscle Res Cell Motil. 2020 03; 41(1):1-2. PMID: 31865487
     
  4. Pavadai E, Rynkiewicz MJ, Ghosh A, Lehman W. Docking Troponin T onto the Tropomyosin Overlapping Domain of Thin Filaments. Biophys J. 2020 01 21; 118(2):325-336.View Related Profiles. PMID: 31864661
     
  5. Egge N, Arneaud SLB, Wales P, Mihelakis M, McClendon J, Fonseca RS, Savelle C, Gonzalez I, Ghorashi A, Yadavalli S, Lehman WJ, Mirzaei H, Douglas PM. Age-Onset Phosphorylation of a Minor Actin Variant Promotes Intestinal Barrier Dysfunction. Dev Cell. 2019 12 02; 51(5):587-601.e7. PMID: 31794717
     
  6. Janco M, Rynkiewicz MJ, Li L, Hook J, Eiffe E, Ghosh A, Böcking T, Lehman WJ, Hardeman EC, Gunning PW. Molecular integration of the anti-tropomyosin compound ATM-3507 into the coiled coil overlap region of the cancer-associated Tpm3.1. Sci Rep. 2019 08 02; 9(1):11262.View Related Profiles. PMID: 31375704
     
  7. Lehman W, Moore JR, Campbell SG, Rynkiewicz MJ. The Effect of Tropomyosin Mutations on Actin-Tropomyosin Binding: In Search of Lost Time. Biophys J. 2019 06 18; 116(12):2275-2284.View Related Profiles. PMID: 31130236
     
  8. Lehman W, Rynkiewicz MJ, Moore JR. A new twist on tropomyosin binding to actin filaments: perspectives on thin filament function, assembly and biomechanics. J Muscle Res Cell Motil. 2020 03; 41(1):23-38.View Related Profiles. PMID: 30771202
     
  9. Kiani FA, Lehman W, Fischer S, Rynkiewicz MJ. Spontaneous transitions of actin-bound tropomyosin toward blocked and closed states. J Gen Physiol. 2019 01 07; 151(1):4-8.View Related Profiles. PMID: 30442774
     
  10. Lehman W, Li X, Kiani FA, Moore JR, Campbell SG, Fischer S, Rynkiewicz MJ. Precise Binding of Tropomyosin on Actin Involves Sequence-Dependent Variance in Coiled-Coil Twisting. Biophys J. 2018 09 18; 115(6):1082-1092.View Related Profiles. PMID: 30195938
     
Showing 10 of 176 results. Show More

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

Bar chart showing 159 publications over 41 distinct years, with a maximum of 13 publications in 2011

YearPublications
19802
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19822
19832
19841
19851
19862
19871
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19902
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19951
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200911
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201311
20149
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20195
20203

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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