Shirin Akhter, Zhiling Zhang, J-P Jin
Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
American journal of physiology. Heart and circulatory physiology 2012 Feb 15In addition to the core structure conserved in all troponin I isoforms, cardiac troponin I (cTnI) has an ∼30 amino acids NH(2)-terminal extension. This peptide segment is a heart-specific regulatory structure containing two Ser residues that are substrates of PKA. Under β-adrenergic regulation, phosphorylation of cTnI in the NH(2)-terminal extension increases the rate of myocardial relaxation. The NH(2)-terminal extension of cTnI is also removable by restrictive proteolysis to produce functional adaptation to hemodynamic stresses. The molecular mechanism for the NH(2)-terminal modifications to regulate the function of cTnI is not fully understood. In the present study, we tested a hypothesis that the NH(2)-terminal extension functions by modulating the conformation of other regions of cTnI. Monoclonal antibody epitope analysis and protein binding experiments demonstrated that deletion of the NH(2)-terminal segment altered epitopic conformation in the middle, but not COOH-terminal, region of cTnI. PKA phosphorylation produced similar effects. This targeted long-range conformational modulation corresponded to changes in the binding affinities of cTnI for troponin T and for troponin C in a Ca(2+)-dependent manner. The data suggest that the NH(2)-terminal extension of cTnI regulates cardiac muscle function through modulating molecular conformation and function of the core structure of cTnI.
Shirin Akhter, Zhiling Zhang, J-P Jin. The heart-specific NH2-terminal extension regulates the molecular conformation and function of cardiac troponin I. American journal of physiology. Heart and circulatory physiology. 2012 Feb 15;302(4):H923-33
PMID: 22140044
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