title: Biochemical characterisation of Troponin C mutations causing hypertrophic and dilated cardiomyopathies.
abstract: Cardiac muscle contraction occurs through an interaction of the myosin head with the actin filaments, a process which is regulated by the troponin complex together with tropomyosin and is Ca(2+) dependent. Mutations in genes encoding sarcomeric proteins are a common cause of familial hypertrophic and dilated cardiomyopathies. The scope of this review is to gather information from studies regarding the in vitro characterisation of six HCM and six DCM mutations on the cardiac TnC gene and to suggest, if possible, how they may lead to dysfunction. Since TnC is the subunit responsible for Ca(2+) binding, mutations in the TnC could possibly have a strong impact on Ca(2+) binding affinities. Furthermore, the interactions of mutant TnCs with their binding partners could be altered. From the characterisation studies available to date, we can conclude that the HCM mutations on TnC increase significantly the Ca(2+) sensitivity of force development or of ATPase activity, producing large pCa shifts in comparison to WT TnC. In contrast, the DCM mutations on TnC have a tendency to decrease the Ca(2+) sensitivity of force development or of ATPase activity in comparison to WT TnC. Furthermore, the DCM mutants of TnC are not responsive to the TnI phosphorylation signal resulting in filaments that preserve their Ca(2+) sensitivity in contrast to WT filaments that experience a decrease in Ca(2+) sensitivity upon TnI phosphorylation.
authors.affiliation: Molecular Cardiology Laboratory, Department of Cardiology, School of Medicine, University of Crete, Crete, Greece, natasa.kalyva@gmail.com.
authors.forename: Athanasia
authors.initials: A
authors.lastname: Kalyva
authors.forename: Fragiskos I
authors.initials: FI
authors.lastname: Parthenakis
authors.forename: Maria E
authors.initials: ME
authors.lastname: Marketou
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Kontaraki
authors.forename: Panos E
authors.initials: PE
authors.lastname: Vardas
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D014335:Tropomyosin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019209:Troponin C / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D014335:Tropomyosin; D019209:Troponin C; D002118:Calcium
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