PUBLICATION

A Single Serine in the Carboxyl Terminus of Cardiac Essential Myosin Light Chain-1 Controls Cardiomyocyte Contractility In Vivo

Authors
Meder, B., Laufer, C., Hassel, D., Just, S., Marquart, S., Vogel, B., Hess, A., Fishman, M.C., Katus, H.A., and Rottbauer, W.
ID
ZDB-PUB-090204-16
Date
2009
Source
Circulation research   104(5): 650-659 (Journal)
Registered Authors
Fishman, Mark C., Hassel, David, Hess, Alexander, Just, Steffen, Laufer, Christina, Marquart, Sabine, Meder, Benjamin, Rottbauer, Wolfgang, Vogel, Britta
Keywords
zebrafish, genetics, essential cardiac myosin light chain-1, phosphorylation, myocardial contractility
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cloning, Molecular
  • Codon, Nonsense
  • Ethylnitrosourea/toxicity
  • Gene Expression Regulation, Developmental
  • Genotype
  • Heart/drug effects
  • Heart/embryology*
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Muscle Strength
  • Mutagens/toxicity
  • Myocardial Contraction*/genetics
  • Myocytes, Cardiac/drug effects
  • Myocytes, Cardiac/metabolism*
  • Myosin Light Chains/chemistry
  • Myosin Light Chains/genetics
  • Myosin Light Chains/metabolism*
  • Phenotype
  • Phosphorylation
  • Protein Stability
  • Protein Structure, Tertiary
  • Sarcomeres/metabolism
  • Sequence Homology, Amino Acid
  • Serine
  • Time Factors
  • Zebrafish
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed
19168438 Full text @ Circ. Res.
Abstract
Although it is well known that mutations in the cardiac essential myosin light chain-1 (cmlc-1) gene can cause hypertrophic cardiomyopathy, the precise in vivo structural and functional roles of cMLC-1 in the heart are only poorly understood. We have isolated the zebrafish mutant lazy susan (laz), which displays severely reduced contractility of both heart chambers. By positional cloning, we identified a nonsense mutation within the zebrafish cmlc-1 gene to be responsible for the laz phenotype, leading to expression of a carboxyl-terminally truncated cMLC-1. Whereas complete loss of cMLC-1 leads to cardiac acontractility attributable to impaired cardiac sarcomerogenesis, expression of a carboxyl-terminally truncated cMLC-1 in laz mutant hearts is sufficient for normal cardiac sarcomerogenesis but severely impairs cardiac contractility in a cell-autonomous fashion. Whereas overexpression of wild-type cMLC-1 restores contractility of laz mutant cardiomyocytes, overexpression of phosphorylation site serine 195-deficient cMLC-1 (cMLC-1(S195A)) does not reconstitute cardiac contractility in laz mutant cardiomyocytes. By contrast, introduction of a phosphomimetic amino acid on position 195 (cMLC-1(S195D)) rescues cardiomyocyte contractility, demonstrating for the first time an essential role of the carboxyl terminus and especially of serine 195 of cMLC-1 in the regulation of cardiac contractility.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes