Cardiac myosin binding protein C phosphorylation affects cross-bridge cycle's elementary steps in a site-specific manner

Li Wang; Sakthivel Sadayappan; Masakata Kawai

doi:10.1371/journal.pone.0113417

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Cardiac myosin binding protein C phosphorylation affects cross-bridge cycle's elementary steps in a site-specific manner

Journal article

Open access

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Cardiac myosin binding protein C phosphorylation affects cross-bridge cycle's elementary steps in a site-specific manner

Li Wang, Sakthivel Sadayappan and Masakata Kawai

PloS one, Vol.9(11), pp.e113417-e113417

2014

DOI: 10.1371/journal.pone.0113417

PMCID: PMC4242647

PMID: 25420047

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Abstract

Based on our recent finding that cardiac myosin binding protein C (cMyBP-C) phosphorylation affects muscle contractility in a site-specific manner, we further studied the force per cross-bridge and the kinetic constants of the elementary steps in the six-state cross-bridge model in cMyBP-C mutated transgenic mice for better understanding of the influence of cMyBP-C phosphorylation on contractile functions. Papillary muscle fibres were dissected from cMyBP-C mutated mice of ADA (Ala273-Asp282-Ala302), DAD (Asp273-Ala282-Asp302), SAS (Ser273-Ala282-Ser302), and t/t (cMyBP-C null) genotypes, and the results were compared to transgenic mice expressing wide-type (WT) cMyBP-C. Sinusoidal analyses were performed with serial concentrations of ATP, phosphate (Pi), and ADP. Both t/t and DAD mutants significantly reduced active tension, force per cross-bridge, apparent rate constant (2πc), and the rate constant of cross-bridge detachment. In contrast to the weakened ATP binding and enhanced Pi and ADP release steps in t/t mice, DAD mice showed a decreased ADP release without affecting the ATP binding and the Pi release. ADA showed decreased ADP release, and slightly increased ATP binding and cross-bridge detachment steps, whereas SAS diminished the ATP binding step and accelerated the ADP release step. t/t has the broadest effects with changes in most elementary steps of the cross-bridge cycle, DAD mimics t/t to a large extent, and ADA and SAS predominantly affect the nucleotide binding steps. We conclude that the reduced tension production in DAD and t/t is the result of reduced force per cross-bridge, instead of the less number of strongly attached cross-bridges. We further conclude that cMyBP-C is an allosteric activator of myosin to increase cross-bridge force, and its phosphorylation status modulates the force, which is regulated by variety of protein kinases.

Phosphorylation

Muscle Contraction - genetics

Heart - physiology

Genotype

Mice, Transgenic

Adenosine Diphosphate - pharmacology

Adenosine Triphosphate - pharmacology

Carrier Proteins - genetics

Phosphates - metabolism

Algorithms

Animals

Carrier Proteins - metabolism

Muscle Contraction - drug effects

Adenosine Triphosphate - metabolism

Muscle Contraction - physiology

Papillary Muscles - physiology

Papillary Muscles - metabolism

Heart Ventricles - metabolism

Adenosine Diphosphate - metabolism

Kinetics

Mutation

Phosphates - pharmacology

Details

Title: Subtitle: Cardiac myosin binding protein C phosphorylation affects cross-bridge cycle's elementary steps in a site-specific manner
Creators: Li Wang - Department of Anatomy and Cell Biology, College of Medicine, University of Iowa, Iowa City, Iowa, United States of America; School of Nursing, Soochow University, Suzhou, Jiangsu, China
Sakthivel Sadayappan - Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, Illinois, United States of America
Masakata Kawai - Department of Anatomy and Cell Biology, College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Resource Type: Journal article
Publication Details: PloS one, Vol.9(11), pp.e113417-e113417
DOI: 10.1371/journal.pone.0113417
PMID: 25420047
PMCID: PMC4242647
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: R01 HL070041 / NHLBI NIH HHS R01 HL105826 / NHLBI NIH HHS K02HL114749 / NHLBI NIH HHS R01HL105826 / NHLBI NIH HHS K02 HL114749 / NHLBI NIH HHS HL070041 / NHLBI NIH HHS
Language: English
Date published: 2014
Academic Unit: Anatomy and Cell Biology; Internal Medicine
Record Identifier: 9984025353502771

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