Dilated cardiomyopathy mutations in α-tropomyosin inhibit its movement during the ATPase cycle

The Glu40Lys and Glu54Lys mutations in α-tropomyosin cause dilated cardiomyopathy (DCM). Functional analysis has demonstrated that both mutations decrease thin filament Ca 2+-sensitivity and that Glu40Lys reduces maximum activation. To understand the molecular mechanism underlying these changes, we...

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Bibliographic Details
Published in:	Biochemical and biophysical research communications Vol. 381; no. 3; pp. 403 - 406
Main Authors:	Borovikov, Yurii S., Karpicheva, Olga E., Chudakova, Galina A., Robinson, Paul, Redwood, Charles S.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 10-04-2009
Subjects:	Actins - metabolism Adenosine Triphosphatases - metabolism ATPase cycle Cardiomyopathy, Dilated - genetics Cardiomyopathy, Dilated - metabolism Dilated cardiomyopathy Ghost muscle fibers Humans Mutation Polarized fluorescence Tropomyosin - genetics Tropomyosin - metabolism α-Tropomyosin Ghost muscle fibers Dilated cardiomyopathy 5-IAF ATPase cycle Polarized fluorescence TM TN α-Tropomyosin S1 DCM
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Summary:	The Glu40Lys and Glu54Lys mutations in α-tropomyosin cause dilated cardiomyopathy (DCM). Functional analysis has demonstrated that both mutations decrease thin filament Ca 2+-sensitivity and that Glu40Lys reduces maximum activation. To understand the molecular mechanism underlying these changes, we labeled wild type α-tropomyosin and both mutants at Cys190 with 5-iodoacetamide-fluorescein and incorporated the labeled proteins into ghost muscle fibers. Using the polarized fluorimetry, the position of the labeled tropomyosins on the thin filament and their affinity for actin were measured and the change in these parameters at different stages of the ATPase cycle determined. Both DCM mutations were found to shift tropomyosin towards the periphery of thin filament and to change the affinity of tropomyosin for actin; during the ATPase cycle the amplitude of tropomyosin movement was reduced and at some stages of the cycle even reversed. The correlation of these structural changes with the observed function effects is discussed.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0006-291X 1090-2104
DOI:	10.1016/j.bbrc.2009.02.054