title: Several cardiomyopathy causing mutations on tropomyosin either destabilize the active state of actomyosin or alter the binding properties of tropomyosin.
abstract: We examined the cardiomyopathy-causing tropomyosin mutations E180G, D175N, and V95A to determine their effects on actomyosin regulation. V95A reduced the ATPase rate when filaments were saturated with regulatory proteins both in the presence and absence of calcium, indicating either a stabilization of the inactive state or an inability to fully populate the active state. Effects of E180G and D175N were more complex. These two mutations increased ATPase rates at sub-saturating concentrations of troponin and tropomyosin as compared to wild type tropomyosin. At higher concentrations of regulatory proteins, ATPase rates became similar to wild type. Normal activation was achieved with the tight-binding myosin analog N-ethylmaleimide-S1, at saturating regulatory protein concentrations. These results suggest that the E180G and D175N mutations reduce the affinity of tropomyosin for actin and also destabilize troponin binding to the actin thin filaments.
authors.affiliation: Department of Biochemistry and Molecular Biology, 600 Moye Blvd., Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA. mohitcmathur@yahoo.com
authors.forename: Mohit C
authors.initials: MC
authors.lastname: Mathur
authors.forename: P Bryant
authors.initials: PB
authors.lastname: Chase
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Chalovich
mesh_terms: D000205:Actomyosin / Q000737:chemistry / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D011817:Rabbits; D014335:Tropomyosin / Q000235:genetics*
chemical_list: D014335:Tropomyosin; D000205:Actomyosin; D000251:Adenosine Triphosphatases; D002118:Calcium