title: Early-Onset Hypertrophic Cardiomyopathy Mutations Significantly Increase the Velocity, Force, and Actin-Activated ATPase Activity of Human β-Cardiac Myosin.
abstract: Hypertrophic cardiomyopathy (HCM) is a heritable cardiovascular disorder that affects 1 in 500 people. A significant percentage of HCM is attributed to mutations in β-cardiac myosin, the motor protein that powers ventricular contraction. This study reports how two early-onset HCM mutations, D239N and H251N, affect the molecular biomechanics of human β-cardiac myosin. We observed significant increases (20%-90%) in actin gliding velocity, intrinsic force, and ATPase activity in comparison to wild-type myosin. Moreover, for H251N, we found significantly lower binding affinity between the S1 and S2 domains of myosin, suggesting that this mutation may further increase hyper-contractility by releasing active motors. Unlike previous HCM mutations studied at the molecular level using human β-cardiac myosin, early-onset HCM mutations lead to significantly larger changes in the fundamental biomechanical parameters and show clear hyper-contractility.
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Arjun S
authors.initials: AS
authors.lastname: Adhikari
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kristina B
authors.initials: KB
authors.lastname: Kooiker
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Saswata S
authors.initials: SS
authors.lastname: Sarkar
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Spudich
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: kruppel@stanford.edu.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Ruppel
mesh_terms: D000199:Actins / Q000235:genetics* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000503:physiopathology; D005838:Genotype; D006801:Humans; D020409:Molecular Motor Proteins / Q000235:genetics*; D009154:Mutation; D009200:Myocardial Contraction / Q000235:genetics; D024723:Ventricular Myosins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D000199:Actins; D020409:Molecular Motor Proteins; D000251:Adenosine Triphosphatases; D024723:Ventricular Myosins
keywords: HCM; hypertrophic cardiomyopathy; in vitro motility; molecular motors; myosin; single molecule