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

Abbott, Maxwell Bret
http://rave.ohiolink.edu/etdc/view?acc_num=ucin999026020

Abstract Details

2001, PhD, University of Cincinnati, Medicine : Molecular Genetics, Biochemistry and Microbiology.
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.
Paul Rosevear (Advisor)
1 p.
CARDIAC TROPONIN; PROTEIN-PROTEIN INTERACTIONS; NUCLEAR MAGNETIC; STRUCTURE - FUNCTION; PHOSPHORYLATION

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Citations

  • Abbott, M. B. (2001). THE STRUCTURAL MECHANISM OF Β-ADRENERGIC MODULATION OF CARDIAC TROPONIN SWITCH CALCIUM SENSITIVITY [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin999026020

    APA Style (7th edition)

  • Abbott, Maxwell. THE STRUCTURAL MECHANISM OF Β-ADRENERGIC MODULATION OF CARDIAC TROPONIN SWITCH CALCIUM SENSITIVITY. 2001. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin999026020.

    MLA Style (8th edition)

  • Abbott, Maxwell. "THE STRUCTURAL MECHANISM OF Β-ADRENERGIC MODULATION OF CARDIAC TROPONIN SWITCH CALCIUM SENSITIVITY." Doctoral dissertation, University of Cincinnati, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=ucin999026020

    Chicago Manual of Style (17th edition)

ucin999026020
© 2001, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.