Altered cardiac troponin T in vitro function in the presence of a mutation implicated in familial hypertrophic cardiomyopathy.
Familial hypertrophic cardiomyopathy (HCM) can be caused by dominant missense mutations in cardiac troponin T (TnT), alpha-tropomyosin, C-protein, or cardiac myosin heavy chain genes. The myosin mutations are known to impair function, but any functional consequences of the TnT mutations are unknown. This report describes the in vitro function of troponin containing an IIe91Asn mutation in rat cardiac TnT, corresponding to the HCM-causing Ile79Asn mutation in man. Mutant and wild-type TnT cDNAs were expressed in bacteria and the proteins purified and reconstituted with the other troponin subunits, the mutation had no effect on troponin's affinity for tropomyosin, troponin-induced binding of tropomyosin to actin, cooperative binding of myosin subfragment 1 to the thin filament, CA(2+)-sensitive regulation of thin filament-myosin subfragment 1 ATPase activity, or the CA2+ concentration dependence of this regulation. However, the mutation resulted in 50% faster thin filament movement over a surface coated with heavy meromyosin in in vitro motility assays. The increased sliding speed suggests an unexpected role for the amino terminal region of TnT in which this mutation occurs. The relationship between this faster motility and altered cardiac contraction in patients with HCM is discussed.
Lin
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Department of Internal Medicine, University of Iowa, Iowa City 52242, USA.
Bobkova
A
A
Homsher
E
E
Tobacman
L S
LS
D000199:Actins / Q000378:metabolism; D000818:Animals; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002417:Cattle; D006801:Humans; D009154:Mutation; D015879:Myosin Subfragments / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D014335:Tropomyosin / Q000378:metabolism; D014336:Troponin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020107:Troponin T
D000199:Actins; D015879:Myosin Subfragments; D014335:Tropomyosin; D014336:Troponin; D020107:Troponin T; D017301:Ca(2+) Mg(2+)-ATPase; D002118:Calcium