The contraction of skeletal, cardiac and smooth muscles occurs by an ATP dependent interaction of the proteins myosin and actin. These same proteins are also required for several critical processes, such as cell division, in nonmuscle cells. The force producing interaction between actin and myosin is regulated by changes in either myosin or actin. Whereas skeletal and cardiac muscle are regulated primarily through the actin filament, by the proteins tropomyosin and troponin, smooth muscle has been thought to be regulated by the level of phosphorylation of myosin. Evidence from several laboratories suggest that smooth muscle contraction may also be modulated by actin binding proteins. Two proteins implicated in this activity are caldesmon and calponin. Both proteins are known to inhibit the high rate of ATP hydrolysis that occurs in the presence of both myosin and actin. We hope to determine the mechanism by which these proteins function and make particular note of differences with the tropomyosin-troponin system of skeletal and cardiac muscle. This will be done by determining the effect of these proteins, individually and in combination, on the binding of various chemical states of myosin to actin. We will also use stopped flow kinetic measurements to determine the effect of these proteins on key transitions between actomyosin states. We also hope to demonstrate the function of these proteins in smooth muscle cells. Differences in regulation from skeletal and cardiac muscle may be exploited for the intervention of hypertension, uterine disorders, digestive disorders or other disorders involving smooth muscle contraction.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Lymn, Richard W
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East Carolina University
Schools of Medicine
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Kingsbury, Nathanial L; Renegar, Randall H; Chalovich, Joseph M (2013) Avian synaptopodin 2 (fesselin) stabilizes myosin filaments and actomyosin in the presence of ATP. Biochemistry 52:7641-7
Schroeter, Mechthild M; Orlova, Albina; Egelman, Edward H et al. (2013) Organization of F-actin by Fesselin (avian smooth muscle synaptopodin 2). Biochemistry 52:4955-61
Franklin, Andrew J; Baxley, Tamatha; Kobayashi, Tomoyoshi et al. (2012) The C-terminus of troponin T is essential for maintaining the inactive state of regulated actin. Biophys J 102:2536-44
Jung, Hyun Suk; Billington, Neil; Thirumurugan, Kavitha et al. (2011) Role of the tail in the regulated state of myosin 2. J Mol Biol 408:863-78
Chalovich, Joseph M; Lutz, Evan; Baxley, Tamatha et al. (2011) Acrylodan-labeled smooth muscle tropomyosin reports differences in the effects of troponin and caldesmon in the transition from the active state to the inactive state. Biochemistry 50:6093-101
Chalovich, Joseph M; Schroeter, Mechthild M (2010) Synaptopodin family of natively unfolded, actin binding proteins: physical properties and potential biological functions. Biophys Rev 2:181-189
Varughese, Jayson F; Chalovich, Joseph M; Li, Yumin (2010) Molecular dynamics studies on troponin (TnI-TnT-TnC) complexes: insight into the regulation of muscle contraction. J Biomol Struct Dyn 28:159-74
Hamden, Svetlana S; Schroeter, Mechthild M; Chalovich, Joseph M (2010) Phosphorylation of caldesmon at sites between residues 627 and 642 attenuates inhibitory activity and contributes to a reduction in Ca2+-calmodulin affinity. Biophys J 99:1861-8
Renegar, Randall H; Chalovich, Joseph M; Leinweber, Barbara D et al. (2009) Localization of the actin-binding protein fesselin in chicken smooth muscle. Histochem Cell Biol 131:191-6
Jung, Hyun Suk; Burgess, Stan A; Billington, Neil et al. (2008) Conservation of the regulated structure of folded myosin 2 in species separated by at least 600 million years of independent evolution. Proc Natl Acad Sci U S A 105:6022-6

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