Structural and protein interaction effects of hypertrophic and dilated cardiomyopathic mutations in alpha-tropomyosin

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 w...

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Published inFrontiers in physiology Vol. 5; p. 460
Main Authors Chang, Audrey N, Greenfield, Norma J, Singh, Abhishek, Potter, James D, Pinto, Jose R
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 2014
Subjects
actomyosin ATPase
cardiomyopathy
Circular Dichroism
Molecular modeling
Physiology
Thermal denaturation
tropomyosin structure
thermal denaturation
actomyosin ATPase
circular dichroism
cardiomyopathy
molecular modeling
tropomyosin structure
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Summary: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.
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Reviewed by: Seth L. Robia, Loyola University Chicago, USA; Ranganath Mamidi, Case Western Reserve University, USA
This article was submitted to Striated Muscle Physiology, a section of the journal Frontiers in Physiology.
Present address: Audrey N. Chang, Department of Physiology, University of Texas Southwestern Medical Center, Dallas, USA
Edited by: Kenneth S. Campbell, University of Kentucky, USA
ISSN:1664-042X
1664-042X
DOI:10.3389/fphys.2014.00460