Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 552, Issue -, Pages 3-10Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2013.12.001
Keywords
Troponin I; C-terminal end-segment; Myofilament regulation; Restrictive cardiomyopathy; Striated muscle
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Funding
- National Heart, Lung and Blood Institute and National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [HL098945, AR048816]
- Office of Vice President for Research, Wayne State University
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The C-terminal end-segment of Troponin I (TnI) corresponding to the last 27-33 amino acids is the most conserved structure of TnI and interacts with tropomyosin in a Ca2+-regulated manner, suggesting a role in muscle relaxation. Mutations in the C-terminal end-segment of cardiac TnI cause restrictive cardiomyopathy. Here we demonstrate that mouse cardiac TnI containing R193H or R205H mutation have significantly conformational changes in the region interfacing with troponin T (TnT) and increased binding affinity for TnT. These restrictive cardiomyopathy mutations also exhibit increased binding affinity for troponin Cat pCa 4. The effects of R193H mutation were more profound than that of R205H. Tertiary troponin complex was reconstituted using the TnI mutants and a mini TnT lacking tropomyosin-binding sites to examine the interaction between the C-terminal end-segment of TnI and tropomyosin. The results showed that, R193H, but not R205H, caused a moderate but statistically significant increase in the binding affinity for tropomyosin at pCa 9. Similar trend was observed at pCa 5.5 but not pCa 4. These results provide novel evidence for the function of the C-terminal end-segment of TnI, where mutations with conformational effects alter TnI's interaction with other troponin subunits and tropomyosin to cause diastolic dysfunction. (C) 2013 Published by Elsevier Inc.
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