Thermodynamic Investigation into the Binding Properties of Cardiac Troponin (Human and Bovine)

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Zachary Haulsee (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Troponin is an integral protein in the mechanism of muscle contraction. In order to induce cardiac muscle contraction, Ca2+ must bind to the TnC subunit (calcium binding subunit) of troponin to begin a conformational change in the protein. The ATPase rate of myosin with actin present is cooperatively activated by Ca2+ and Myosin. Ca2+ greatly increases the rate of ATPase activity (18-fold) and decreases the concentration of actin needed for muscle contraction activity. Ca2+ binding to troponin induces a conformational change that leads to a process of muscle contraction [8].  The focus of our research has been to investigate thermodynamic binding properties of various divalent metals to the Troponin C subunit of the cardiac muscle protein using isothermal titration calorimetry. We have been able to successfully observe Ca2+ binding to the apo form of Bovine Cardiac TnC (BVCTnC) as well as the apo form of Human Cardiac TnC (HCTnC).   Familial Hypertrophic Cardiomyopathy, FHCM, is an autosomal dominant genetic disorder. FHCM causes an abnormal cardiac muscle contraction response in patients afflicted with the genetic mutations that result in the disorder. About 1 in 500 people, 0.2%, are afflicted with this disorder. There are many ways to approach treatment for this disease. A treatment that we have considered uses calcium sensitizing drugs. Calcium sensitizing drugs allow troponin to be more sensitive to the presence of calcium which induces cardiac muscle contraction [31].  Another focus of our research is to determine thermodynamic binding properties of calcium sensitizing drugs to troponin using isothermal titration calorimetry. Understanding the thermodynamic properties of drug-protein interaction can help reveal the mechanism of action by which the drug operates. These studies will lead to a better understanding of how calcium sensitizing drugs interact with troponin and determine their practicality in drug design for patients afflicted with familial hypertrophic cardiomyopathies.  

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Date: 2010

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