ZFIN ID: ZDB-PUB-090204-16
A Single Serine in the Carboxyl Terminus of Cardiac Essential Myosin Light Chain-1 Controls Cardiomyocyte Contractility In Vivo
Meder, B., Laufer, C., Hassel, D., Just, S., Marquart, S., Vogel, B., Hess, A., Fishman, M.C., Katus, H.A., and Rottbauer, W.
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.
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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.
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