Correlation of molecular and functional effects of mutations in cardiac troponin T linked to familial hypertrophic cardiomyopathy: an integrative in silico/in vitro approach.

The Journal of Biological Chemistry
Edward P ManningJil C Tardiff

Abstract

Nearly 70% of all of the known cTnT mutations that cause familial hypertrophic cardiomyopathy fall within the TNT1 region that is critical to cTn-Tm binding. The high resolution structure of this domain has not been determined, and this lack of information has hindered structure-function analysis. In the current study, a coupled computational experimental approach was employed to correlate changes in cTnT dynamics to basic function using the regulated in vitro motility assay (R-IVM). An in silico approach to calculate forces in terms of a bending coordinate was used to precisely identify decreases in bending forces at residues 105 and 106 within the proposed cTnT "hinge" region. Significant functional changes were observed in multiple functional properties, including a decrease in the cooperativity of calcium activation, the calcium sensitivity of sliding speed, and maximum sliding speed. Correlation of the computational and experimental findings revealed an association between TNT1 flexibility and the cooperativity of thin filament calcium activation where an increase in flexibility led to a decrease in cooperativity. Further analysis of the primary sequence of the TNT1 region revealed a unique pattern of conserved charged TNT...Continue Reading

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Citations

Oct 16, 2012·The Journal of Biological Chemistry·Devanand Kowlessur, Larry S Tobacman
Aug 14, 2012·Journal of Molecular and Cellular Cardiology·Steven J FordMurali Chandra
Mar 10, 2016·Proceedings of the National Academy of Sciences of the United States of America·Michael R WilliamsSteven D Schwartz
May 15, 2012·Journal of Molecular Biology·Edward P ManningSteven D Schwartz
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Jul 22, 2020·Proceedings of the National Academy of Sciences of the United States of America·Aditi MadanAnthony Cammarato
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