| http://purl.uniprot.org/citations/34051236 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/34051236 | http://www.w3.org/2000/01/rdf-schema#comment | "Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder primarily caused by mutations in the β-myosin heavy-chain gene. The proximal subfragment 2 region (S2), 126 amino acids of myosin, binds with the C0-C2 region of cardiac myosin-binding protein-C to regulate cardiac muscle contractility in a manner dependent on PKA-mediated phosphorylation. However, it is unknown if HCM-associated mutations within S2 dysregulate actomyosin dynamics by disrupting its interaction with C0-C2, ultimately leading to HCM. Herein, we study three S2 mutations known to cause HCM: R870H, E924K, and E930Δ. First, experiments using recombinant proteins, solid-phase binding, and isothermal titrating calorimetry assays independently revealed that mutant S2 proteins displayed significantly reduced binding with C0-C2. In addition, CD revealed greater instability of the coiled-coil structure in mutant S2 proteins compared with S2Wt proteins. Second, mutant S2 exhibited 5-fold greater affinity for PKA-treated C0-C2 proteins. Third, skinned papillary muscle fibers treated with mutant S2 proteins showed no change in the rate of force redevelopment as a measure of actin-myosin cross-bridge kinetics, whereas S2Wt showed increased the rate of force redevelopment. In summary, S2 and C0-C2 interaction mediated by phosphorylation is altered by mutations in S2, which augment the speed and force of contraction observed in HCM. Modulating this interaction could be a potential strategy to treat HCM in the future."xsd:string |
| http://purl.uniprot.org/citations/34051236 | http://purl.org/dc/terms/identifier | "doi:10.1016/j.jbc.2021.100836"xsd:string |
| http://purl.uniprot.org/citations/34051236 | http://purl.uniprot.org/core/author | "McNamara J.W."xsd:string |
| http://purl.uniprot.org/citations/34051236 | http://purl.uniprot.org/core/author | "Singh R.R."xsd:string |
| http://purl.uniprot.org/citations/34051236 | http://purl.uniprot.org/core/author | "Sadayappan S."xsd:string |
| http://purl.uniprot.org/citations/34051236 | http://purl.uniprot.org/core/date | "2021"xsd:gYear |
| http://purl.uniprot.org/citations/34051236 | http://purl.uniprot.org/core/name | "J Biol Chem"xsd:string |
| http://purl.uniprot.org/citations/34051236 | http://purl.uniprot.org/core/pages | "100836"xsd:string |
| http://purl.uniprot.org/citations/34051236 | http://purl.uniprot.org/core/title | "Mutations in myosin S2 alter cardiac myosin-binding protein-C interaction in hypertrophic cardiomyopathy in a phosphorylation-dependent manner."xsd:string |
| http://purl.uniprot.org/citations/34051236 | http://purl.uniprot.org/core/volume | "297"xsd:string |
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