Cardiomyopathic mutations in essential light chain reveal mechanisms regulating the super relaxed state of 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:
19
10
2020
revised:
06
04
2021
accepted:
27
04
2021
entrez:
20
5
2021
pubmed:
21
5
2021
medline:
16
10
2021
Statut:
ppublish
Résumé
In this study, we assessed the super relaxed (SRX) state of myosin and sarcomeric protein phosphorylation in two pathological models of cardiomyopathy and in a near-physiological model of cardiac hypertrophy. The cardiomyopathy models differ in disease progression and severity and express the hypertrophic (HCM-A57G) or restrictive (RCM-E143K) mutations in the human ventricular myosin essential light chain (ELC), which is encoded by the MYL3 gene. Their effects were compared with near-physiological heart remodeling, represented by the N-terminally truncated ELC (Δ43 ELC mice), and with nonmutated human ventricular WT-ELC mice. The HCM-A57G and RCM-E143K mutations had antagonistic effects on the ATP-dependent myosin energetic states, with HCM-A57G cross-bridges fostering the disordered relaxed (DRX) state and the RCM-E143K model favoring the energy-conserving SRX state. The HCM-A57G model promoted the switch from the SRX to DRX state and showed an ∼40% increase in myosin regulatory light chain (RLC) phosphorylation compared with the RLC of normal WT-ELC myocardium. On the contrary, the RCM-E143K-associated stabilization of the SRX state was accompanied by an approximately twofold lower level of myosin RLC phosphorylation compared with the RLC of WT-ELC. Upregulation of RLC phosphorylation was also observed in Δ43 versus WT-ELC hearts, and the Δ43 myosin favored the energy-saving SRX conformation. The two disease variants also differently affected the duration of force transients, with shorter (HCM-A57G) or longer (RCM-E143K) transients measured in electrically stimulated papillary muscles from these pathological models, while no changes were displayed by Δ43 fibers. We propose that the N terminus of ELC (N-ELC), which is missing in the hearts of Δ43 mice, works as an energetic switch promoting the SRX-to-DRX transition and contributing to the regulation of myosin RLC phosphorylation in full-length ELC mice by facilitating or sterically blocking RLC phosphorylation in HCM-A57G and RCM-E143K hearts, respectively.
Identifiants
pubmed: 34014247
pii: 212172
doi: 10.1085/jgp.202012801
pmc: PMC8142263
pii:
doi:
Substances chimiques
Myosin Light Chains
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL143830
Pays : United States
Organisme : NHLBI NIH HHS
ID : R56 HL146133
Pays : United States
Informations de copyright
© 2021 Sitbon et al.
Références
Circulation. 2020 Mar 10;141(10):828-842
pubmed: 31983222
J Mol Med (Berl). 2014 Nov;92(11):1119-28
pubmed: 24957262
Elife. 2017 Jun 13;6:
pubmed: 28606303
J Physiol. 2003 Sep 1;551(Pt 2):491-501
pubmed: 12824444
J Mol Cell Cardiol. 2018 Aug;121:190-204
pubmed: 30031815
PLoS One. 2011;6(7):e21746
pubmed: 21799747
J Mol Biol. 2016 Mar 27;428(6):1142-1164
pubmed: 26851071
Cardiovasc Res. 2012 Jan 1;93(1):79-88
pubmed: 22012956
Cardiovasc Res. 2017 Mar 15;113(4):411-421
pubmed: 28395011
J Biol Chem. 2005 Oct 14;280(41):34427-34
pubmed: 16085933
Physiol Rep. 2017 Mar;5(6):
pubmed: 28325789
Am Heart J. 2001 Feb;141(2):184-9
pubmed: 11174330
Mol Biol Cell. 2008 Aug;19(8):3234-42
pubmed: 18495867
Nat Protoc. 2012 May 31;7(6):1235-46
pubmed: 22653162
Biochimie. 2003 Jul;85(7):639-45
pubmed: 14505818
J Struct Biol. 2007 Jul;159(1):158-63
pubmed: 17498971
J Cell Sci. 2005 Aug 15;118(Pt 16):3675-83
pubmed: 16076902
Pflugers Arch. 2019 May;471(5):683-699
pubmed: 30706179
Trends Genet. 2003 May;19(5):263-8
pubmed: 12711218
FASEB J. 2011 Dec;25(12):4394-405
pubmed: 21885653
Am J Physiol Heart Circ Physiol. 2013 Aug 15;305(4):H575-89
pubmed: 23748425
Open Biol. 2018 Apr;8(4):
pubmed: 29669825
Circ Arrhythm Electrophysiol. 2013 Aug;6(4):e58-63
pubmed: 23962865
Science. 1993 Jul 2;261(5117):50-8
pubmed: 8316857
N Engl J Med. 2000 Jun 15;342(24):1778-85
pubmed: 10853000
Cardiovasc Res. 2017 Aug 1;113(10):1124-1136
pubmed: 28371863
Biophys J. 2017 Jul 11;113(1):91-100
pubmed: 28700929
Biol Open. 2021 Feb 15;10(2):
pubmed: 33589442
Biophys Rev. 2015 Mar;7(1):5-14
pubmed: 28509977
Nat Commun. 2018 Oct 1;9(1):4019
pubmed: 30275503
Circ Res. 2010 Oct 1;107(7):825-38
pubmed: 20884884
Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12403-7
pubmed: 7809049
J Cell Mol Med. 2012 Apr;16(4):911-9
pubmed: 21696541
J Muscle Res Cell Motil. 2015 Dec;36(6):447-61
pubmed: 26668058
Biochem J. 2009 May 27;420(3):439-49
pubmed: 19338496
J Mol Biol. 2009 Apr 3;387(3):706-25
pubmed: 19361417
Biochemistry. 2016 Jan 12;55(1):186-98
pubmed: 26671638
J Mol Cell Cardiol. 2014 Jul;72:231-7
pubmed: 24726887
J Biol Chem. 2017 May 12;292(19):7774-7783
pubmed: 28330871
Basic Res Cardiol. 1998;93 Suppl 3:13-6
pubmed: 9879437
Adv Protein Chem. 2005;71:161-93
pubmed: 16230112
N Engl J Med. 1997 Jan 23;336(4):267-76
pubmed: 8995091
Eur J Biochem. 1998 Aug 1;255(3):654-62
pubmed: 9738905
J Gen Physiol. 2010 Jul;136(1):21-7
pubmed: 20584889
Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):E2338-E2347
pubmed: 29463717
Am J Med Genet A. 2011 Sep;155A(9):2229-35
pubmed: 21823217
FEBS J. 2019 Jan;286(1):151-168
pubmed: 30430732
Biochem J. 2011 Apr 15;435(2):297-312
pubmed: 21726199
Physiol Rev. 2008 Apr;88(2):611-38
pubmed: 18391175
Biochim Biophys Acta. 2010 Jan;1802(1):100-10
pubmed: 19682572
J Biol Chem. 2015 Apr 24;290(17):10703-16
pubmed: 25733667
Eur J Biochem. 1987 Apr 1;164(1):259-66
pubmed: 3549306
Proc Natl Acad Sci U S A. 2016 May 24;113(21):E3039-47
pubmed: 27162358
Proc Natl Acad Sci U S A. 2015 Jul 28;112(30):E4138-46
pubmed: 26124132
FEBS J. 2020 Sep;287(18):3989-4004
pubmed: 32034976
J Vis Exp. 2015 Feb 07;(96):
pubmed: 25741892
Circulation. 2019 Oct 01;140(14):1205-1216
pubmed: 31769940
Front Physiol. 2014 Sep 22;5:353
pubmed: 25295008
Curr Protoc Hum Genet. 2009 Oct;Chapter 19:Unit19.3
pubmed: 19806590
J Mol Med (Berl). 2019 Jul;97(7):1033-1047
pubmed: 31101927
Circulation. 2002 May 21;105(20):2337-40
pubmed: 12021217
Biophys Rev. 2017 Feb;9(1):57-64
pubmed: 28510043
Biophys J. 2011 Apr 20;100(8):1969-76
pubmed: 21504733
Proc Natl Acad Sci U S A. 2020 Apr 7;117(14):8177-8186
pubmed: 32220962
Nature. 1990 Nov 15;348(6298):217-21
pubmed: 2234090
Cell Death Differ. 2015 Feb;22(2):248-57
pubmed: 25323588
Physiol Rep. 2017 Feb;5(3):
pubmed: 28193782
J Biol Chem. 2009 Feb 20;284(8):5097-106
pubmed: 19106098
Hum Mol Genet. 2002 Oct 1;11(20):2499-506
pubmed: 12351586