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Am J Physiol Heart Circ Physiol. 2012 Feb 15;302(4):H923-33. doi: 10.1152/ajpheart.00637.2011. Epub 2011 Dec 2.

The heart-specific NH2-terminal extension regulates the molecular conformation and function of cardiac troponin I.

Author information

1
Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.

Abstract

In 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.

PMID:
22140044
PMCID:
PMC3322736
DOI:
10.1152/ajpheart.00637.2011
[Indexed for MEDLINE]
Free PMC Article

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