Document Detail

A single serine in the carboxyl terminus of cardiac essential myosin light chain-1 controls cardiomyocyte contractility in vivo.
MedLine Citation:
PMID:  19168438     Owner:  NLM     Status:  MEDLINE    
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.
Benjamin Meder; Christina Laufer; David Hassel; Steffen Just; Sabine Marquart; Britta Vogel; Alexander Hess; Mark C Fishman; Hugo A Katus; Wolfgang Rottbauer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-01-22
Journal Detail:
Title:  Circulation research     Volume:  104     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2009 Mar 
Date Detail:
Created Date:  2009-03-16     Completed Date:  2009-04-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  650-9     Citation Subset:  IM    
Department of Medicine III, University of Heidelberg, Heidelberg, Germany.
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MeSH Terms
Amino Acid Sequence
Base Sequence
Cloning, Molecular
Codon, Nonsense
Ethylnitrosourea / toxicity
Gene Expression Regulation, Developmental
Heart / drug effects,  embryology*
Models, Molecular
Molecular Conformation
Molecular Sequence Data
Muscle Strength
Mutagens / toxicity
Myocardial Contraction* / genetics
Myocytes, Cardiac / drug effects,  metabolism*
Myosin Light Chains / chemistry,  genetics,  metabolism*
Protein Stability
Protein Structure, Tertiary
Sarcomeres / metabolism
Sequence Homology, Amino Acid
Time Factors
Zebrafish Proteins / chemistry,  genetics,  metabolism*
Reg. No./Substance:
0/Cmlc1 protein, zebrafish; 0/Codon, Nonsense; 0/Mutagens; 0/Myosin Light Chains; 0/Zebrafish Proteins; 56-45-1/Serine; 759-73-9/Ethylnitrosourea

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