Impact of regulatory light chain mutation K104E on the ATPase and motor properties of cardiac myosin

David V. Rasicci, Orville Kirkland, Faruk H. Moonschi, Neil B. Wood, Danuta Szczesna-Cordary, Michael J. Previs, Jonathan F. Wenk, Kenneth S. Campbell, Christopher M. Yengo

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Mutations in the cardiac myosin regulatory light chain (RLC, MYL2 gene) are known to cause inherited cardiomyopathies with variable phenotypes. In this study, we investigated the impact of a mutation in the RLC (K104E) that is associated with hypertrophic cardiomyopathy (HCM). Previously in a mouse model of K104E, older animals were found to develop cardiac hypertrophy, fibrosis, and diastolic dysfunction, suggesting a slow development of HCM. However, variable penetrance of the mutation in human populations suggests that the impact of K104E may be subtle. Therefore, we generated human cardiac myosin subfragment-1 (M2β-S1) and exchanged on either the wild type (WT) or K104E human ventricular RLC in order to assess the impact of the mutation on the mechanochemical properties of cardiac myosin. The maximum actin-activated ATPase activity and actin sliding velocities in the in vitro motility assay were similar in M2β-S1 WT and K104E, as were the detachment kinetic parameters, including the rate of ATP-induced dissociation and the ADP release rate constant. We also examined the mechanical performance of α-cardiac myosin extracted from transgenic (Tg) mice expressing human wild type RLC (Tg WT) or mutant RLC (Tg K104E). We found that α-cardiac myosin from Tg K104E animals demonstrated enhanced actin sliding velocities in the motility assay compared with its Tg WT counterpart. Furthermore, the degree of incorporation of the mutant RLC into α-cardiac myosin in the transgenic animals was significantly reduced compared with wild type. Therefore, we conclude that the impact of the K104E mutation depends on either the length or the isoform of the myosin heavy chain backbone and that the mutation may disrupt RLC interactions with the myosin lever arm domain.

Original languageEnglish
Article numbere202012811
JournalJournal of General Physiology
Issue number7
StatePublished - Jul 5 2021

Bibliographical note

Publisher Copyright:
© 2021 Rasicci et al.


  • 2020
  • Biophysics
  • Contraction and cell motility
  • Molecular physiology
  • Myofilament special issue

ASJC Scopus subject areas

  • Physiology


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