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Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform.

ABSTRACT: Tropomyosin (TM), an essential actin-binding protein, is central to the control of calcium-regulated striated muscle contraction. Although TPM1alpha (also called alpha-TM) is the predominant TM isoform in human hearts, the precise TM isoform composition remains unclear.In this study, we quantified for the first time the levels of striated muscle TM isoforms in human heart, including a novel isoform called TPM1kappa. By developing a TPM1kappa-specific antibody, we found that the TPM1kappa protein is expressed and incorporated into organized myofibrils in hearts and that its level is increased in human dilated cardiomyopathy and heart failure. To investigate the role of TPM1kappa in sarcomeric function, we generated transgenic mice overexpressing cardiac-specific TPM1kappa. Incorporation of increased levels of TPM1kappa protein in myofilaments leads to dilated cardiomyopathy. Physiological alterations include decreased fractional shortening, systolic and diastolic dysfunction, and decreased myofilament calcium sensitivity with no change in maximum developed tension. Additional biophysical studies demonstrate less structural stability and weaker actin-binding affinity of TPM1kappa compared with TPM1alpha.This functional analysis of TPM1kappa provides a possible mechanism for the consequences of the TM isoform switch observed in dilated cardiomyopathy and heart failure patients.

SUBMITTER: Rajan S

PROVIDER: S-EPMC2822663 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform.

Rajan Sudarsan S Jagatheesan Ganapathy G Karam Chehade N CN Alves Marco L ML Bodi Ilona I Schwartz Arnold A Bulcao Christian F CF D'Souza Karen M KM Akhter Shahab A SA Boivin Greg P GP Dube Dipak K DK Petrashevskaya Natalia N Herr Andrew B AB Hullin Roger R Liggett Stephen B SB Wolska Beata M BM Solaro R John RJ Wieczorek David F DF

Circulation 20100111 3

<h4>Background</h4>Tropomyosin (TM), an essential actin-binding protein, is central to the control of calcium-regulated striated muscle contraction. Although TPM1alpha (also called alpha-TM) is the predominant TM isoform in human hearts, the precise TM isoform composition remains unclear.<h4>Methods and results</h4>In this study, we quantified for the first time the levels of striated muscle TM isoforms in human heart, including a novel isoform called TPM1kappa. By developing a TPM1kappa-specifi ...[more]

PMID: 20065163

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Project description:Troponin I (TnI) is the molecular switch of the sarcomere. Cardiac myocytes express two isoforms of TnI during development. The fetal heart expresses the slow skeletal TnI (ssTnI) isoform and shortly after birth ssTnI is completely and irreversibly replaced by the adult cardiac TnI (cTnI) isoform. These two isoforms have important functional differences; broadly, ssTnI is a positive inotrope, especially under acidic/hypoxic conditions, whereas cTnI facilitates faster relaxation performance. Evolutionary directed changes in cTnI sequence suggest cTnI evolved to favor relaxation performance in the mammalian heart. To investigate the mechanism, we focused on several notable TnI isoform and trans-species-specific residues located in TnI's helix 4 using structure/function and molecular dynamics analyses. Gene transduction of adult cardiac myocytes by cTnIs with specific helix 4 ssTnI substitutions, Q157R/A164H/E166V/H173N (QAEH), and A164H/H173N (AH), were investigated. cTnI QAEH is similar in these four residues to ssTnI and nonmammalian chordate cTnIs, whereas cTnI AH is similar to fish cTnI in these four residues. In comparison to mammalian cTnI, cTnI QAEH and cTnI AH showed increased contractility and slowed relaxation, which functionally mimicked ssTnI expressing myocytes. cTnI QAEH molecular dynamics simulations demonstrated altered intermolecular interactions between TnI helix 4 and cTnC helix A, specifically revealing a new, to our knowledge, electrostatic interaction between R171of cTnI and E15 of cTnC, which structurally phenocopied the ssTnI conformation. Free energy perturbation calculation of cTnC Ca(2+) binding for these conformations showed relative increased calcium binding for cTnI QAEH compared to cTnI. Taken together, to our knowledge, these new findings provide evidence that the evolutionary-directed coordinated acquisition of residues Q157, A164, E166, H173 facilitate enhanced relaxation performance in mammalian adult cardiac myocytes.

Dataset Information

Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform.

Publications

Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform.

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