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J. Biol. Chem., Vol. 279, Issue 14, 13825-13832, April 2, 2004

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An R111C Polymorphism in Wild Turkey Cardiac Troponin I Accompanying the Dilated Cardiomyopathy-related Abnormal Splicing Variant of Cardiac Troponin T with Potentially Compensatory Effects^*

Brandon J. Biesiadecki, Kristi L. Schneider, Zhi-Bin Yu, Stephen M. Chong, and Jian-Ping Jin¶

From the Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970

Cardiac muscle contraction is regulated by Ca²⁺ through the troponin complex consisting of three subunits: troponin C (TnC), troponin T (TnT), and troponin I (TnI). We reported previously that 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, R111C. 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 -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 Escherichia coli were performed. The results show that the R111C 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.

Received for publication, December 28, 2003 , and in revised form, January 20, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY463242, AY463243, and AY463244.

^* This study was supported in part by National Aeronautics and Space Administration Grant NAG 2-1598 and by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR 048816 (to J.-P. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Postdoctoral Fellowship 0325266B from the American Heart Association Northeast Ohio Affiliate.

Supported in part by a Howard Hughes Summer Undergraduate Research Program at Case Western Reserve University.

^¶ To whom correspondence should be addressed. Tel.: 216-368-5525; Fax: 216-368-3952; E-mail: jxj12{at}po.cwru.edu.

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