RGD Reference Report - Functional and spectroscopic studies of a familial hypertrophic cardiomyopathy mutation in Motif X of cardiac myosin binding protein-C. - Rat Genome Database

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Functional and spectroscopic studies of a familial hypertrophic cardiomyopathy mutation in Motif X of cardiac myosin binding protein-C.

Authors: Brown, LJ  Singh, L  Sale, KL  Yu, B  Trent, R  Fajer, PG  Hambly, BD 
Citation: Brown LJ, etal., Eur Biophys J. 2002 Sep;31(5):400-8. Epub 2002 Jun 25.
RGD ID: 1580236
Pubmed: PMID:12202917   (View Abstract at PubMed)
DOI: DOI:10.1007/s00249-002-0236-0   (Journal Full-text)

Familial hypertrophic cardiomyopathy is an autosomal dominant genetic disorder caused by mutations in cardiac sarcomeric proteins. One such mutation is a six amino acid duplication of residues 1248-1253 in the C-terminal immunoglobulin domain of cardiac myosin binding protein-C, referred to as Motif X. Motif X binds the myosin rod and titin. Here we investigate the structural and functional alteration in the mutant Motif X protein to understand how sarcomeric dysfunction may occur. The cDNA encoding Motif X was cloned, mutated and expressed as wild-type and mutant proteins in a bacterial expression system. Circular dichroism spectroscopy confirmed that the normal and mutant Motif X exhibited a high beta-content, as predicted for immunoglobulin domains. Thermal denaturation curves showed that Motif X unfolded with at least two structural transitions, with the first transition occurring at 63 degrees C in the wild-type but at 40 degrees C in the mutant, consistent with the mutant being structurally less stable. Sedimentation binding studies with synthetic myosin filaments revealed no significant difference in binding to myosin between the wild-type and the mutant Motif X. Molecular modeling of this duplication mutation onto an homologous IgI structure (telokin) revealed that the duplicated residues lie within the F strand of the immunoglobulin fold, on a surface of Motif X distant from residues previously implicated in myosin binding. Taken together, these data suggest that the Motif X mutation may interfere with other, as yet unidentified, functional interactions.

Objects referenced in this article
Gene MYBPC3 myosin binding protein C3 Homo sapiens
Gene Mybpc3 myosin binding protein C, cardiac Mus musculus
Gene Mybpc3 myosin binding protein C3 Rattus norvegicus

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