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
- Princeton University, PhD
- State University of New York at Stony Brook, BS
- Published on 2/15/2019
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. 2019 Feb 15. PMID: 30771202.
- Published on 11/15/2018
Kiani FA, Lehman W, Fischer S, Rynkiewicz MJ. Spontaneous transitions of actin-bound tropomyosin toward blocked and closed states. J Gen Physiol. 2019 Jan 07; 151(1):4-8. PMID: 30442774.
- Published on 8/18/2018
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 Sep 18; 115(6):1082-1092. PMID: 30195938.
- Published on 4/5/2018
Farman GP, Rynkiewicz MJ, Orzechowski M, Lehman W, Moore JR. HCM and DCM cardiomyopathy-linked a-tropomyosin mutations influence off-state stability and crossbridge interaction on thin filaments. Arch Biochem Biophys. 2018 06 01; 647:84-92. PMID: 29626422.
- Published on 1/1/2018
Viswanathan MC, Schmidt W, Madan A, Sullivan LC, Newhard CS, Rynkiewicz MJ, Lehman W, Swank DM, Cammarato A. The ACTC M305L Hypertrophic Cardiomyopathy Mutation Results in Hypercontractility and Impaired Relaxation of Drosophila Muscles. Biophysical Journal. 2018; 114(3):315a.
- Published on 1/1/2018
Kiani FA, Rynkiewicz MJ, Fischer S, Lehman W. Tropomyosin Translocation on F-Actin Revealed by Molecular Dynamics Simulations. Biophysical Journal. 2018; 114(3):136a.
- Published on 1/1/2018
Sewanan L, Park J, Rynkiewicz MJ, Hollenberg SM, Papoutsidakis N, Jacoby D, Moore JR, Lehman W, Qyang Y, Campbell SG. Pathogenic Mechanisms of the Cardiomyopathy-Associated Alpha-Tropomyosin Variant E192K as Revealed by Multiscale Modeling and Experiments. Biophysical Journal. 2018; 114(3):495a.
- Published on 12/5/2017
Rynkiewicz MJ, Prum T, Hollenberg S, Kiani FA, Fagnant PM, Marston SB, Trybus KM, Fischer S, Moore JR, Lehman W. Tropomyosin Must Interact Weakly with Actin to Effectively Regulate Thin Filament Function. Biophys J. 2017 Dec 05; 113(11):2444-2451. PMID: 29211998.
- Published on 9/12/2017
Viswanathan MC, Schmidt W, Rynkiewicz MJ, Agarwal K, Gao J, Katz J, Lehman W, Cammarato A. Distortion of the Actin A-Triad Results in Contractile Disinhibition and Cardiomyopathy. Cell Rep. 2017 Sep 12; 20(11):2612-2625. PMID: 28903042.
- Published on 5/25/2017
Lehman W. Switching Muscles On and Off in Steps: The McKillop-Geeves Three-State Model of Muscle Regulation. Biophys J. 2017 06 20; 112(12):2459-2466. PMID: 28552313.
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