Modulation of thin filament activation of myosin ATP hydrolysis by N-terminal domains of cardiac myosin binding protein-C

Betty Belknap, Samantha P. Harris, Howard D. White

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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-Pi 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 pCa > 8 but has little effect on the activation mechanism at pCa = 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.

Original languageEnglish (US)
Pages (from-to)6717-6724
Number of pages8
JournalBiochemistry
Volume53
Issue number42
DOIs
StatePublished - Oct 28 2014
Externally publishedYes

Fingerprint

Cardiac Myosins
Myosins
Hydrolysis
Adenosine Triphosphate
Chemical activation
Modulation
Actins
Adenosine Triphosphatases
Actomyosin
Enzyme kinetics
Phosphorylation
Sarcomeres
Cyclic AMP-Dependent Protein Kinases
myosin-binding protein C
Adenosine Diphosphate
Serine
Actin Cytoskeleton
Swine

ASJC Scopus subject areas

  • Biochemistry
  • Medicine(all)

Cite this

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.

In: Biochemistry, Vol. 53, No. 42, 28.10.2014, p. 6717-6724.

Research output: Contribution to journalArticle

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. In: Biochemistry. 2014 ; Vol. 53, No. 42. pp. 6717-6724.
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