Effect of Hypertrophic Cardiomyopathy Mutations in Human Cardiac Muscle α -tropomyosin (Asp175Asn and Glu180Gly) on the Regulatory Properties of Human Cardiac Troponin Determined by in vitro Motility Assay

Bing, Wu; Knott, Adam; Redwood, Charles; Esposito, Giovanna; Purcell, Ian; Watkins, Hugh; Marston, Steven B.

doi:10.1006/jmcc.2000.1182

Cited by 65 publications

(54 citation statements)

References 31 publications

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“…TnT mutants that showed no change in sliding velocity when tested with human ␤-cardiac myosin showed significant changes when tested with non-human myosins (33). The D175N HCM Tm mutant produced no change in Ca 2ϩ sensitivity when assayed in rat or bovine contexts (51,52), but it increased Ca 2ϩ sensitivity when assayed using rabbit fast skeletal heavy meromyosin (53). When the R453C HCM mutant was produced in mouse ␣-cardiac MHC (54) and human ␤-cardiac MHC (55), there was a similar increase in single-molecule force production.…”

Section: Discussionmentioning

confidence: 98%

Mechanistic Heterogeneity in Contractile Properties of α-Tropomyosin (TPM1) Mutants Associated with Inherited Cardiomyopathies

Gupte

Haque

Gangadharan

et al. 2015

Journal of Biological Chemistry

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Background: Single residue substitutions in sarcomeric proteins cause most inherited cardiomyopathies. Results: Mutant ␣-tropomyosins cause multiple functional alterations in actin affinity and Ca 2ϩ sensitivity. Conclusion: Mutants follow distinct mechanisms to change Ca 2ϩ sensitivity. Significance: Fluorescence assays to measure changes in troponin C conformation may provide a simple platform for preliminary high throughput screening of modulatory small molecules to treat inherited cardiomyopathies.

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Section: Discussionmentioning

confidence: 98%

Mechanistic Heterogeneity in Contractile Properties of α-Tropomyosin (TPM1) Mutants Associated with Inherited Cardiomyopathies

Gupte

Haque

Gangadharan

et al. 2015

Journal of Biological Chemistry

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“…E180G also caused a loss in the stability of the Tm structure when thermal denaturation was measured by circular dichroism and differential scanning calorimetry (32,33). In addition, E180G-Tm caused a decrease in thin filament motility when measured by in vitro motility assays (31,34). In vivo studies of transgenic mice expressing this mutation showed a severe phenotype of hypertrophy, myocardial disarray, and detrimental effects on contraction and relaxation (35,36).…”

Section: Discussionmentioning

confidence: 99%

Functional Consequences of Hypertrophic and Dilated Cardiomyopathy-causing Mutations in α-Tropomyosin

Chang

Harada

Ackerman

et al. 2005

Journal of Biological Chemistry

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To study the functional consequences of various cardiomyopathic mutations in human cardiac ␣-tropomyosin (Tm), a method of depletion/reconstitution of native Tm and troponin (Tn) complex (Tm-Tn) in cardiac myofibril preparations has been developed. The endogenous Tm-Tn complex was selectively removed from myofibrils and replaced with recombinant wild-type or mutant proteins. Successful depletion and reconstitution steps were verified by SDS-gel electrophoresis and by the loss and regain of Ca 2؉ -dependent regulation of ATPase activity. Five Tm mutations were chosen for this study: the hypertrophic cardiomyopathy (HCM) mutations E62Q, E180G, and L185R and the dilated cardiomyopathy (DCM) mutations E40K and E54K. Through the use of this new depletion/ reconstitution method, the functional consequences of these mutations were determined utilizing myofibrillar ATPase measurements. The results of our studies showed that 1) depletion of >80% of Tm-Tn from myofibrils resulted in a complete loss of the Ca 2؉ -regulated ATPase activity and a significant loss in the maximal ATPase activity, 2) reconstitution of exogenous wild-type Tm-Tn resulted in complete regain in the calcium regulation and in the maximal ATPase activity, and 3) all HCM-associated Tm mutations increased the Ca 2؉ sensitivity of ATPase activity and all had decreased abilities to inhibit ATPase activity. In contrast, the DCMassociated mutations both decreased the Ca 2؉ sensitivity of ATPase activity and had no effect on the inhibition of ATPase activity. These findings have demonstrated that the mutations which cause HCM and DCM disrupt discrete mechanisms, which may culminate in the distinct cardiomyopathic phenotypes.

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“…As with D53, these mutations map within the tropomyosin region which interacts with TnT in a Ca 2ϩ -sensitive manner. In vitro motility experiments using reconstituted cardiac thin filaments showed that these HCM mutations affect the Ca 2ϩ sensitivity of the fraction of filaments moving compared with wild-type, although in the absence of structural information on the Ca 2ϩ -sensitive Tm binding site for TnT, it is not clear how these mutations could cause this (Bing et al, 2000). There is evidence that HCM TnT mutations, I79N and R92Q, located within the same TnT-Tm interaction (residues 70 -180) may affect Ca 2ϩ sensitivity in tension versus force measurements (see Tobacman et al, 1999 for discussion).…”

Section: Discussionmentioning

confidence: 99%

A Tropomyosin-2 Mutation Suppresses a Troponin I Myopathy inDrosophila

Naïmi

Harrison

Cummins

et al. 2001

MBoC

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A suppressor mutation, D53, of the held-up 2 allele of the Drosophila melanogaster Troponin I (wupA) gene is described. D53, a missense mutation, S185F, of the tropomyosin-2, Tm2, gene fully suppresses all the phenotypic effects of held-up 2 , including the destructive hypercontraction of the indirect flight muscles (IFMs), a lack of jumping, the progressive myopathy of the walking muscles, and reductions in larval crawling and feeding behavior. The suppressor restores normal function of the IFMs, but flight ability decreases with age and correlates with an unusual, progressive structural collapse of the myofibrillar lattice starting at the center. The S185F substitution in Tm2 is close to a troponin T binding site on tropomyosin. Models to explain suppression by D53, derived from current knowledge of the vertebrate troponin-tropomyosin complex structure and functions, are discussed. The effects of S185F are compared with those of two mutations in residues 175 and 180 of human ␣-tropomyosin 1 which cause familial hypertrophic cardiomyopathy (HCM).

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Effect of Hypertrophic Cardiomyopathy Mutations in Human Cardiac Muscle α -tropomyosin (Asp175Asn and Glu180Gly) on the Regulatory Properties of Human Cardiac Troponin Determined by in vitro Motility Assay

Cited by 65 publications

References 31 publications

Mechanistic Heterogeneity in Contractile Properties of α-Tropomyosin (TPM1) Mutants Associated with Inherited Cardiomyopathies

Mechanistic Heterogeneity in Contractile Properties of α-Tropomyosin (TPM1) Mutants Associated with Inherited Cardiomyopathies

Functional Consequences of Hypertrophic and Dilated Cardiomyopathy-causing Mutations in α-Tropomyosin

A Tropomyosin-2 Mutation Suppresses a Troponin I Myopathy inDrosophila

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