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
- Princeton University, PhD
- State University of New York at Stony Brook, BS
- Published on 4/4/2018
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 Apr 04. PMID: 29626422.
- 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.
- Published on 10/26/2016
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. PMID: 27833562.
- Published on 9/20/2016
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. PMID: 27663225.
- Published on 3/15/2016
Lehman W. Thin Filament Structure and the Steric Blocking Model. Compr Physiol. 2016 Mar 15; 6(2):1043-69. PMID: 27065174.
- Published on 2/15/2016
Moore JR, Campbell SG, Lehman W. Structural determinants of muscle thin filament cooperativity. Arch Biochem Biophys. 2016 Mar 15; 594:8-17. PMID: 26891592.
- Published on 1/14/2016
Fischer S, Rynkiewicz MJ, Moore JR, Lehman W. Tropomyosin diffusion over actin subunits facilitates thin filament assembly. Struct Dyn. 2016 Jan; 3(1):012002. PMID: 26798831.
- Published on 8/19/2015
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. PMID: 26286845.
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