Effects of a Cardiomyopathy-causing Troponin T Mutation on Thin Filament Function and Structure

Familial hypertrophic cardiomyopathy (FHC) is caused by missense or premature truncation mutations in proteins of the cardiac contractile apparatus. Mutant proteins are incorporated into the thin filament or thick filament and eventually produce cardiomyopathy. However, it has been unclear how the s...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-06, Vol.276 (23), p.20788-20794
Main Authors: Burhop, James, Rosol, Michael, Craig, Roger, Tobacman, Larry S., Lehman, William
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Cardiomyopathies - genetics
Cattle
Familial hypertrophic cardiomyopathy
Microscopy, Electron
Mutation
Protein Conformation
Rabbits
Troponin T - genetics
Troponin T - metabolism
Troponin T - ultrastructure
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Summary:Familial hypertrophic cardiomyopathy (FHC) is caused by missense or premature truncation mutations in proteins of the cardiac contractile apparatus. Mutant proteins are incorporated into the thin filament or thick filament and eventually produce cardiomyopathy. However, it has been unclear how the several, genetically identified defects in protein structure translate into impaired protein and muscle function. We have studied the basis of FHC caused by premature truncation of the most frequently implicated thin filament target, troponin T. Electron microscope observations showed that the thin filament undergoes normal structural changes in response to Ca2+ binding. On the other hand, solution studies showed that the mutation alters and destabilizes troponin binding to the thin filament to different extents in different regulatory states, thereby affecting the transitions among states that regulate myosin binding and muscle contraction. Development of hypertrophic cardiomyopathy can thus be traced to a defect in the primary mechanism controlling cardiac contraction, switching between different conformations of the thin filament.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M101110200