Cargando…

Modulation of Thin Filament Activation of Myosin ATP Hydrolysis by N-Terminal Domains of Cardiac Myosin Binding Protein-C

[Image: see text] We have used enzyme kinetics to investigate the molecular mechanism by which the N-terminal domains of human and mouse cardiac MyBP-C (C0C1, C1C2, and C0C2) affect the activation of myosin ATP hydrolysis by F-actin and by native porcine thin filaments. N-Terminal domains of cMyBP-C...

Descripción completa

Detalles Bibliográficos
Autores principales: Belknap, Betty, Harris, Samantha P., White, Howard D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211651/
https://www.ncbi.nlm.nih.gov/pubmed/25265574
http://dx.doi.org/10.1021/bi500787f
_version_ 1782341603363389440
author Belknap, Betty
Harris, Samantha P.
White, Howard D.
author_facet Belknap, Betty
Harris, Samantha P.
White, Howard D.
author_sort Belknap, Betty
collection PubMed
description [Image: see text] We have used enzyme kinetics to investigate the molecular mechanism by which the N-terminal domains of human and mouse cardiac MyBP-C (C0C1, C1C2, and C0C2) affect the activation of myosin ATP hydrolysis by F-actin and by native porcine thin filaments. N-Terminal domains of cMyBP-C inhibit the activation of myosin-S1 ATPase by F-actin. However, mouse and human C1C2 and C0C2 produce biphasic activating and inhibitory effects on the activation of myosin ATP hydrolysis by native cardiac thin filaments. Low ratios of MyBP-C N-terminal domains to thin filaments activate myosin-S1 ATP hydrolysis, but higher ratios inhibit ATP hydrolysis, as is observed with F-actin alone. These data suggest that low concentrations of C1C2 and C0C2 activate thin filaments by a mechanism similar to that of rigor myosin-S1, whereas higher concentrations inhibit the ATPase rate by competing with myosin-S1-ADP-P(i) for binding to actin and thin filaments. In contrast to C0C2 and C1C2, the activating effects of the C0C1 domain are species-dependent: human C0C1 activates actomyosin-S1 ATPase rates, but mouse C0C1 does not produce significant activation or inhibition. Phosphorylation of serine residues in the m-linker between the C1 and C2 domains by protein kinase-A decreases the activation of thin filaments by huC0C2 at pC(a) > 8 but has little effect on the activation mechanism at pC(a) = 4. In sarcomeres, the low ratio of cMyBP-C to actin is expected to favor the activating effects of cMyBP-C while minimizing inhibition produced by competition with myosin heads.
format Online
Article
Text
id pubmed-4211651
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher American Chemical Society
record_format MEDLINE/PubMed
spelling pubmed-42116512015-09-29 Modulation of Thin Filament Activation of Myosin ATP Hydrolysis by N-Terminal Domains of Cardiac Myosin Binding Protein-C Belknap, Betty Harris, Samantha P. White, Howard D. Biochemistry [Image: see text] We have used enzyme kinetics to investigate the molecular mechanism by which the N-terminal domains of human and mouse cardiac MyBP-C (C0C1, C1C2, and C0C2) affect the activation of myosin ATP hydrolysis by F-actin and by native porcine thin filaments. N-Terminal domains of cMyBP-C inhibit the activation of myosin-S1 ATPase by F-actin. However, mouse and human C1C2 and C0C2 produce biphasic activating and inhibitory effects on the activation of myosin ATP hydrolysis by native cardiac thin filaments. Low ratios of MyBP-C N-terminal domains to thin filaments activate myosin-S1 ATP hydrolysis, but higher ratios inhibit ATP hydrolysis, as is observed with F-actin alone. These data suggest that low concentrations of C1C2 and C0C2 activate thin filaments by a mechanism similar to that of rigor myosin-S1, whereas higher concentrations inhibit the ATPase rate by competing with myosin-S1-ADP-P(i) for binding to actin and thin filaments. In contrast to C0C2 and C1C2, the activating effects of the C0C1 domain are species-dependent: human C0C1 activates actomyosin-S1 ATPase rates, but mouse C0C1 does not produce significant activation or inhibition. Phosphorylation of serine residues in the m-linker between the C1 and C2 domains by protein kinase-A decreases the activation of thin filaments by huC0C2 at pC(a) > 8 but has little effect on the activation mechanism at pC(a) = 4. In sarcomeres, the low ratio of cMyBP-C to actin is expected to favor the activating effects of cMyBP-C while minimizing inhibition produced by competition with myosin heads. American Chemical Society 2014-09-29 2014-10-28 /pmc/articles/PMC4211651/ /pubmed/25265574 http://dx.doi.org/10.1021/bi500787f Text en Copyright © 2014 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html)
spellingShingle Belknap, Betty
Harris, Samantha P.
White, Howard D.
Modulation of Thin Filament Activation of Myosin ATP Hydrolysis by N-Terminal Domains of Cardiac Myosin Binding Protein-C
title Modulation of Thin Filament Activation of Myosin ATP Hydrolysis by N-Terminal Domains of Cardiac Myosin Binding Protein-C
title_full Modulation of Thin Filament Activation of Myosin ATP Hydrolysis by N-Terminal Domains of Cardiac Myosin Binding Protein-C
title_fullStr Modulation of Thin Filament Activation of Myosin ATP Hydrolysis by N-Terminal Domains of Cardiac Myosin Binding Protein-C
title_full_unstemmed Modulation of Thin Filament Activation of Myosin ATP Hydrolysis by N-Terminal Domains of Cardiac Myosin Binding Protein-C
title_short Modulation of Thin Filament Activation of Myosin ATP Hydrolysis by N-Terminal Domains of Cardiac Myosin Binding Protein-C
title_sort modulation of thin filament activation of myosin atp hydrolysis by n-terminal domains of cardiac myosin binding protein-c
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211651/
https://www.ncbi.nlm.nih.gov/pubmed/25265574
http://dx.doi.org/10.1021/bi500787f
work_keys_str_mv AT belknapbetty modulationofthinfilamentactivationofmyosinatphydrolysisbynterminaldomainsofcardiacmyosinbindingproteinc
AT harrissamanthap modulationofthinfilamentactivationofmyosinatphydrolysisbynterminaldomainsofcardiacmyosinbindingproteinc
AT whitehowardd modulationofthinfilamentactivationofmyosinatphydrolysisbynterminaldomainsofcardiacmyosinbindingproteinc