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Papers In Press, published online ahead of print January 20, 2004
Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106-4970
Corresponding Author: jxj12{at}po.cwru.edu
Cardiac muscle contraction is regulated by Ca2+ through the troponin complex consisting of three subunits: troponin C, troponin T (TnT) and troponin I (TnI). We previously reported the abnormal splicing of cardiac TnT in turkeys with dilated cardiomyopathy resulted in a greater binding affinity to TnI. In the present study, we characterized a polymorphism of cardiac TnI in the heart of wild turkeys. cDNA cloning and sequencing of the novel turkey cardiac TnI revealed a single amino acid substitution, Arg111Cys. Arg111 in avian cardiac TnI corresponds to a Lys in mammals. This residue is conserved in cardiac and skeletal muscle TnIs across the vertebrate phylum, implying a functional importance. In the partial crystal structure of cardiac troponin, this amino acid resides in an a-helix that directly contacts with TnT. Structural modeling indicates that the substitution of Cys for Arg or Lys at this position would not disrupt the global structure of troponin. To evaluate the functional significance of the different size and charge between the Arg and Cys side chains, protein-binding assays using purified turkey cardiac TnI expressed in E. coli were performed. The results show that the Arg111Cys substitution lowered binding affinity to TnT, which is potentially compensatory to the increased TnI-binding affinity of the cardiomyopathy-related cardiac TnT splicing variant. Therefore, the fixation of the cardiac TnI Cys111 allele in the wild turkey population and the corresponding functional effect reflect an increased fitness value, suggesting a novel target for the treatment of TnT myopathies.
J. Biol. Chem, 10.1074/jbc.M314225200
Submitted on December 28, 2003
Revised on January 20, 2004
Accepted on January 20, 2004
An Arg111Cys polymorphism in wild turkey cardiac troponin I accompanying the dilated cardiomyopathy-related abnormal splicing variant of cardiac troponin T with potentially compensatory effects
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