THE STRUCTURAL MECHANISM OF Β-ADRENERGIC MODULATION OF CARDIAC TROPONIN SWITCH CALCIUM SENSITIVITY

 
 
 
 

THE STRUCTURAL MECHANISM OF Β-ADRENERGIC MODULATION OF CARDIAC TROPONIN SWITCH CALCIUM SENSITIVITY

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Title: THE STRUCTURAL MECHANISM OF Β-ADRENERGIC MODULATION OF CARDIAC TROPONIN SWITCH CALCIUM SENSITIVITY
Author: Abbott, Maxwell Bret
Description: Cardiac troponin is the molecular switch that activates the cardiac thin filament in response to increased Ca ^2+ concentrations. The sensitivity of the troponin switch to Ca ^2+ is reduced in response to Β-adrenergic hormonal stimulation of the cardiac myocyte, which activates protein kinase A. Protein kinase A phosphorylation of cardiac troponin I decreases the Ca ^2+ binding affinity of cardiac troponin C. The molecular mechanisms of the cardiac troponin switch were investigated by heteronuclear multidimensional NMR and fluorescence techniques. Chemical shift, ^15 N relaxation and translational diffusion studies of various cardiac troponin C/cardiac troponin I complexes revealed cardiac troponin C interaction sites for the inhibitory region of cardiac troponin I and exchange between 'open' and 'closed' conformations of the cardiac troponin C regulatory domain. A cardiac troponin I molecule was engineered to contain aspartate residues at the cardiac troponin I protein kinase A phosphorylation sites to mimic the phosphorylated state. Comparison of chemical shift and dynamic data obtained with this mutant demonstrate interactions between the cardiac specific amino-terminus of troponin I and the troponin C regulatory domain. Chemical shift, dynamic and fluorescence analyses correlate chemical shift changes with conformational opening of cardiac troponin C regulatory domain upon binding the cardiac troponin I regulatory region. The unphosphorylated cardiac specific amino-terminus of troponin I stabilizes the 'open' conformation of the cardiac troponin C regulatory domain. Protein kinase A phosphorylation of cardiac troponin I weakens regulatory interactions between cardiac troponin I and cardiac troponin C. Together the data presented here further our understanding of the mechanism of the cardiac troponin switch and its modulation by protein kinase A phosphorylation.
Permanent Link: http://rave.ohiolink.edu/etdc/view?acc_num=ucin999026020
http://hdl.handle.net/2374.OX/10091
Date: 2001

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