The hypertrophic cardiomyopathy mutations R403Q and R663H increase the number of myosin heads available to interact with actin.
|The hypertrophic cardiomyopathy mutations R403Q and R663H increase the number of myosin heads available to interact with actin.
|Year of Publication
|Sarkar SS, Trivedi DV, Morck MM, Adhikari AS, Pasha SN, Ruppel KM, Spudich JA
Hypertrophic cardiomyopathy (HCM) mutations in β-cardiac myosin and myosin binding protein-C (MyBP-C) lead to hypercontractility of the heart, an early hallmark of HCM. We show that hypercontractility caused by the HCM-causing mutation R663H cannot be explained by changes in fundamental myosin contractile parameters, much like the HCM-causing mutation R403Q. Using enzymatic assays with purified human β-cardiac myosin, we provide evidence that both mutations cause hypercontractility by increasing the number of functionally accessible myosin heads. We also demonstrate that the myosin mutation R403Q, but not R663H, ablates the binding of myosin with the C0-C7 fragment of MyBP-C. Furthermore, addition of C0-C7 decreases the wild-type myosin basal ATPase single turnover rate, while the mutants do not show a similar reduction. These data suggest that a primary mechanism of action for these mutations is to increase the number of myosin heads functionally available for interaction with actin, which could contribute to hypercontractility.
|PubMed Central ID
|R01 GM033289 / GM / NIGMS NIH HHS / United States
R01 HL117138 / HL / NHLBI NIH HHS / United States
UL1 TR001085 / TR / NCATS NIH HHS / United States