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 computational tools such as 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 elucidate 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 to be fearless about the challenge of performing 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 16 papers that have been published by us between 2018 and now (2021), 14 were co-authored by 8 different current or former post-doctoral fellows and 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 have also been engaged in studies on the structural interactions of other actin binding proteins including α-actinin, myosin binding protein-C, 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. (03/17/2021)
- Mentor for Graduate Medical Students, Medical Sciences, Boston Medical Center
- Acting Chair, Physiology & Biophysics, Boston University Chobanian & Avedisian School of Medicine
- Princeton University, PhD
- State University of New York at Stony Brook, BS
- Published on 6/22/2022
Rynkiewicz MJ, Pavadai E, Lehman W. Modeling Human Cardiac Thin Filament Structures. Front Physiol. 2022; 13:932333. PMID: 35812320.
- Published on 5/14/2022
Pavadai E, Rynkiewicz MJ, Yang Z, Gould IR, Marston SB, Lehman W. Modulation of cardiac thin filament structure by phosphorylated troponin-I analyzed by protein-protein docking and molecular dynamics simulation. Arch Biochem Biophys. 2022 Aug 15; 725:109282. PMID: 35577070.
- Published on 2/15/2022
Teekakirikul P, Zhu W, Xu X, Young CB, Tan T, Smith AM, Wang C, Peterson KA, Gabriel GC, Ho S, Sheng Y, Moreau de Bellaing A, Sonnenberg DA, Lin JH, Fotiou E, Tenin G, Wang MX, Wu YL, Feinstein T, Devine W, Gou H, Bais AS, Glennon BJ, Zahid M, Wong TC, Ahmad F, Rynkiewicz MJ, Lehman WJ, Keavney B, Alastalo TP, Freckmann ML, Orwig K, Murray S, Ware SM, Zhao H, Feingold B, Lo CW. Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability. Cell Rep Med. 2022 02 15; 3(2):100501. PMID: 35243414.
- Published on 11/23/2021
Doran MH, Lehman W. The Central Role of the F-Actin Surface in Myosin Force Generation. Biology (Basel). 2021 Nov 23; 10(12). PMID: 34943138.
- Published on 3/11/2021
Lehman W, Pavadai E, Rynkiewicz MJ. C-terminal troponin-I residues trap tropomyosin in the muscle thin filament blocked-state. Biochem Biophys Res Commun. 2021 04 30; 551:27-32. PMID: 33714756.
- Published on 7/16/2020
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 08 18; 119(4):821-830. PMID: 32730789.
- Published on 5/22/2020
Pavadai E, Lehman W, Rynkiewicz MJ. Protein-Protein Docking Reveals Dynamic Interactions of Tropomyosin on Actin Filaments. Biophys J. 2020 07 07; 119(1):75-86. PMID: 32521240.
- Published on 3/1/2020
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.
- Published on 12/6/2019
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. PMID: 31864661.
- Published on 12/2/2019
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.
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