Impact of regulatory light chain mutation K104E on the ATPase and motor properties of cardiac myosin.
Journal
The Journal of general physiology
ISSN: 1540-7748
Titre abrégé: J Gen Physiol
Pays: United States
ID NLM: 2985110R
Informations de publication
Date de publication:
05 07 2021
05 07 2021
Historique:
received:
29
10
2020
accepted:
19
03
2021
entrez:
23
4
2021
pubmed:
24
4
2021
medline:
16
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33891674
pii: 212025
doi: 10.1085/jgp.202012811
pmc: PMC8077168
pii:
doi:
Substances chimiques
Actins
0
Myosin Light Chains
0
Adenosine Triphosphatases
EC 3.6.1.-
Cardiac Myosins
EC 3.6.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : K99 HL124041
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL124041
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL133359
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL127699
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL143830
Pays : United States
Organisme : NHLBI NIH HHS
ID : R56 HL146133
Pays : United States
Informations de copyright
© 2021 Rasicci et al.
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