| First Author | Singh RR | Year | 2021 |
| Journal | J Biol Chem | Volume | 297 |
| Issue | 1 | Pages | 100836 |
| PubMed ID | 34051236 | Mgi Jnum | J:306270 |
| Mgi Id | MGI:6713202 | Doi | 10.1016/j.jbc.2021.100836 |
| Citation | Singh RR, et al. (2021) Mutations in myosin S2 alter cardiac myosin binding protein-C interaction in hypertrophic cardiomyopathy in a phosphorylation-dependent manner. J Biol Chem :100836 |
| abstractText | Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder primarily caused by mutations in the beta-myosin heavy chain gene. The proximal subfragment-2 (S2) region of myosin binds with the C0-C2 region of cardiac myosin binding protein-C (cMyBP-C) to regulate cardiac muscle contractility in a manner dependent on protein kinase A (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 E930Delta. 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, circular dichroism revealed greater instability of the coiled-coil structure in mutant S2 proteins compared to S2(Wt) 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 (ktr) as a measure of actin-myosin cross-bridge kinetics, whereas S2(Wt) showed increased ktr. 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. |
