title: Altered interactions between cardiac myosin binding protein-C and α-cardiac actin variants associated with cardiomyopathies.
abstract: The two genes most commonly associated with mutations linked to hypertrophic or dilated cardiomyopathies are β-myosin and cardiac myosin binding protein-C (cMyBP-C). Both of these proteins interact with cardiac actin (ACTC). Currently there are 16 ACTC variants that have been found in patients with HCM or DCM. While some of these ACTC variants exhibit protein instability or polymerization-deficiencies that might contribute to the development of disease, other changes could cause changes in protein-protein interactions between sarcomere proteins and ACTC. To test the hypothesis that changes in ACTC disrupt interactions with cMyBP-C, we examined the interactions between seven ACTC variants and the N-terminal C0C2 fragment of cMyBP-C. We found there was a significant decrease in binding affinity (increase in Kd values) for the A331P and Y166C variants of ACTC. These results suggest that a change in the ability of cMyBP-C to bind actin filaments containing these ACTC protein variants might contribute to the development of disease. These results also provide clues regarding the binding site of the C0C2 fragment of cMyBP-C on F-actin.
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Chow
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, United States.
authors.forename: Justin F
authors.initials: JF
authors.lastname: Shaffer
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona School of Medicine, Tucson, AZ 85724, United States.
authors.forename: Samantha P
authors.initials: SP
authors.lastname: Harris
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada. Electronic address: jdawso01@uoguelph.ca.
authors.forename: John F
authors.initials: JF
authors.lastname: Dawson
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000473:pathology; D000199:Actins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology; D024723:Ventricular Myosins / Q000235:genetics / Q000378:metabolism*; D000099163:Myosin Binding Protein C
chemical_list: D000199:Actins; D002352:Carrier Proteins; D011994:Recombinant Proteins; D024723:Ventricular Myosins; D000099163:Myosin Binding Protein C
keywords: Cardiac actin; Cardiomyopathy; Heart disease; Myosin binding protein-C
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