Key result
Hypertrophic cardiomyopathy-associated tropomyosin mutants and the dilated cardiomyopathy mutant E54K increased Ca2+-induced maximal actomyosin ATPase activities, whereas the E40K mutant decreased it.
DCM and HCM-associated tropomyosin mutations exert distinct effects on actomyosin ATPase activity and dimer stability, suggesting direct alteration of myosin ATPase rates as a disease mechanism.
Animal findings on tropomyosin mutants should not change cardiomyopathy practice; leaves open mutation-specific ATPase mechanisms for targeted research.
The potential alterations to structure and associations with thin filament proteins caused by the dilated cardiomyopathy (DCM) associated tropomyosin (Tm) mutants E40K and E54K, and the hypertrophic cardiomyopathy (HCM) associated Tm mutants E62Q and L185R, were investigated. In order to ascertain what the cause of the known functional effects may be, structural and protein-protein interaction studies were conducted utilizing actomyosin ATPase activity measurements and spectroscopy. In actomyosin ATPase measurements, both HCM mutants and the DCM mutant E54K caused increases in Ca(2+)-induced maximal ATPase activities, while E40K caused a decrease. Investigation of Tm's ability to inhibit actomyosin ATPase in the absence of troponin showed that HCM-associated mutant Tms did not inhibit as well as wildtype, whereas the DCM associated mutant E40K inhibited better. E54K did not inhibit the actomyosin ATPase activity at any concentration of Tm tested. Thermal denaturation studies by circular dichroism and molecular modeling of the mutations in Tm showed that in general, the DCM mutants caused localized destabilization of the Tm dimers, while the HCM mutants resulted in increased stability. These findings demonstrate that the structural alterations in Tm observed here may affect the regulatory function of Tm on actin, thereby directly altering the ATPase rates of myosin.
No takes yet. Share an insight, caveat, or question.
Chang et al. (2014) studied Dilated and Hypertrophic Cardiomyopathy. Alpha-tropomyosin mutations (E40K, E54K, E62Q, L185R) vs. Wild-type alpha-tropomyosin (ASWT) was evaluated on Actomyosin ATPase activity and thermal stability. Hypertrophic cardiomyopathy-associated tropomyosin mutants and the dilated cardiomyopathy mutant E54K increased Ca2+-induced maximal actomyosin ATPase activities, whereas the E40K mutant decreased it.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: