Myosin motor domains carrying mutations implicated in early or late onset hypertrophic cardiomyopathy have similar properties

Research output: Contribution to journalArticle

Authors

  • Carlos D. Vera
  • Chloe A. Johnson
  • Jonathan Walklate
  • Arjun Adhikari
  • Marina Svicevic
  • Srboljub M. Mijailovich
  • Ariana C. Combs
  • Stephen J. Langer
  • Kathleen M. Ruppel
  • James A. Spudich
  • Michael A. Geeves
  • Leslie A. Leinwand

External Institution(s)

  • University of Colorado Boulder
  • University of Kent
  • University of Kagujevac
  • Illinois Institute of Technology
  • Stanford University

Details

Original languageEnglish (US)
Pages (from-to)17451-17462
Number of pages12
JournalJournal of Biological Chemistry
Volume294
Issue number46
StatusPublished - Nov 15 2019
Peer-reviewedYes

Abstract

Hypertrophic cardiomyopathy (HCM) is a common genetic disorder characterized by left ventricular hypertrophy and cardiac hyper-contractility. Mutations in the β-cardiac myosin heavy chain gene (β-MyHC) are a major cause of HCM, but the specific mechanistic changes to myosin function that lead to this disease remain incompletely understood. Predicting the severity of any β-MyHC mutation is hindered by a lack of detailed examinations at the molecular level. Moreover, because HCM can take ≥20 years to develop, the severity of the mutations must be somewhat subtle. We hypothesized that mutations that result in early onset disease would have more severe changes in function than do later onset mutations. Here, we performed steady-state and transient kinetic analyses of myosins carrying one of seven missense mutations in the motor domain. Of these seven, four were previously identified in early onset cardiomyopathy screens. We used the parameters derived from these analyses to model the ATP-driven cross-bridge cycle. Contrary to our hypothesis, the results indicated no clear differences between early and late onset HCM mutations. Despite the lack of distinction between early and late onset HCM, the predicted occupancy of the force-holding actin·myosin·ADP complex at [Actin] = 3 Kapp along with the closely related duty ratio (the fraction of myosin in strongly attached force-holding states), and the measured ATPases all changed in parallel (in both sign and degree of change) compared with wildtype (WT) values. Six of the seven HCM mutations were clearly distinct from a set of previously characterized DCM mutations.

Citation formats

APA

Vera, C. D., Johnson, C. A., Walklate, J., Adhikari, A., Svicevic, M., Mijailovich, S. M., ... Leinwand, L. A. (2019). Myosin motor domains carrying mutations implicated in early or late onset hypertrophic cardiomyopathy have similar properties. Journal of Biological Chemistry, 294(46), 17451-17462. https://doi.org/10.1074/jbc.RA119.010563

Harvard

Vera, CD, Johnson, CA, Walklate, J, Adhikari, A, Svicevic, M, Mijailovich, SM, Combs, AC, Langer, SJ, Ruppel, KM, Spudich, JA, Geeves, MA & Leinwand, LA 2019, 'Myosin motor domains carrying mutations implicated in early or late onset hypertrophic cardiomyopathy have similar properties', Journal of Biological Chemistry, vol. 294, no. 46, pp. 17451-17462. https://doi.org/10.1074/jbc.RA119.010563