William J. Lehman, PhD
Professor, Pharmacology, Physiology & Biophysics
Biography
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)
Other Positions
- Mentor for Graduate Medical Students, Medical Sciences, Boston Medical Center
Education
- Princeton University, PhD
- State University of New York at Stony Brook, BS
Classes Taught
- MD514
- OH 730
- OH 731
- PH730
- PH731
Publications
- Published on 3/8/2025
Ramachandran B, Rynkiewicz M, Lehman W. Velcro-binding by cardiac troponin-I traps tropomyosin on actin in a low-energy relaxed state. Biochem Biophys Res Commun. 2025 Apr 09; 757:151595. PMID: 40088678.
Read at: PubMed - Published on 3/6/2025
Barry ME, Rynkiewicz MJ, Wen J, Tu AY, Regnier M, Lehman W, Moore JR. Dual role of Tropomyosin-R160 in thin filament regulation: Insights into phosphorylation-dependent cardiac relaxation and cardiomyopathy mechanisms. Arch Biochem Biophys. 2025 Mar 06; 768:110380. PMID: 40057222.
Read at: PubMed - Published on 1/16/2025
Doran MH, Rynkiewicz MJ, Despond E, Viswanathan MC, Madan A, Chitre K, Fenwick AJ, Sousa D, Lehman W, Dawson JF, Cammarato A. The hypertrophic cardiomyopathy-associated A331P actin variant enhances basal contractile activity and elicits resting muscle dysfunction. iScience. 2025 Feb 21; 28(2):111816. PMID: 39981516.
Read at: PubMed - Published on 12/16/2024
Halder SS, Rynkiewicz MJ, Kim L, Barry ME, Zied AG, Sewanan LR, Kirk JA, Moore JR, Lehman WJ, Campbell SG. Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy-associated TPM1 variants. J Clin Invest. 2024 Dec 16; 134(24). PMID: 39436707.
Read at: PubMed - Published on 8/30/2024
Creso JG, Gokhan I, Rynkiewicz MJ, Lehman W, Moore JR, Campbell SG. In silico and in vitro models reveal the molecular mechanisms of hypocontractility caused by TPM1 M8R. Front Physiol. 2024; 15:1452509. PMID: 39282088.
Read at: PubMed - Published on 4/12/2024
Rynkiewicz MJ, Childers MC, Karpicheva OE, Regnier M, Geeves MA, Lehman W. Myosin's powerstroke transitions define atomic scale movement of cardiac thin filament tropomyosin. J Gen Physiol. 2024 May 06; 156(5). PMID: 38607351.
Read at: PubMed - Published on 1/22/2024
Barry ME, Rynkiewicz MJ, Pavadai E, Viana A, Lehman W, Moore JR. Glutamate 139 of tropomyosin is critical for cardiac thin filament blocked-state stabilization. J Mol Cell Cardiol. 2024 Mar; 188:30-37. PMID: 38266978.
Read at: PubMed - Published on 5/30/2023
Lehman W, Rynkiewicz MJ. Troponin-I-induced tropomyosin pivoting defines thin-filament function in relaxed and active muscle. J Gen Physiol. 2023 Jul 03; 155(7). PMID: 37249525.
Read at: PubMed - Published on 1/21/2023
Halder SS, Rynkiewicz MJ, Creso JG, Sewanan LR, Howland L, Moore JR, Lehman W, Campbell SG. Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L. PNAS Nexus. 2023 Mar; 2(3):pgad011. PMID: 36896133.
Read at: PubMed - Published on 1/12/2023
Doran MH, Rynkiewicz MJ, Rassici D, Bodt SML, Barry ME, Bullitt E, Yengo CM, Moore JR, Lehman W. Conformational changes linked to ADP release from human cardiac myosin bound to actin-tropomyosin. J Gen Physiol. 2023 Mar 06; 155(3). PMID: 36633586.
Read at: PubMed
View 189 more publications: View full profile at BUMC