RUI: Quantifying the thermodynamics of Calcium(II) and Cadmium(II) interactions with EF-hand proteins: Understanding the factors that define Cadmium ion mimicry

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With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Elizabeth Smith from Eastern Carolina University to investigate a largely unexplored aspect of the biological chemistry of cadmium. Researchers have mainly focused on cadmium interactions with proteins that contain sulfur atoms as a point of contact. A recent analysis of all available protein structures found that cadmium prefers binding to oxygen rich calcium sites in proteins as well. Interestingly, there is very little data regarding the fundamental driving force for cadmium binding to these proteins therefore creating a large gap in the understanding of such interactions. It is the goal of Dr. Spuches and her students to fill this gap in knowledge regarding cadmium interactions with proteins. Funds provided by the NSF Chemistry of Life Processes Program will allow students in the Spuches lab to conduct a detailed thermodynamic and structural investigation of cadmium binding to natively calcium binding proteins and model peptides. There will be an investigation of a largely unexplored aspect of the biological chemistry of cadmium. The Spuches lab will focus their attention on human cardiac troponin C (HcTnC), an EF-hand protein that utilizes Ca(II) to regulate cardiac muscle contraction. They plan to use a combination of isothermal titration calorimetry (ITC), circular dichroism (CD), and NMR spectroscopy (113Cd/1H) in their studies. The proposed project will provide thermodynamic and structural data on Cd(II) and Ca(II) binding to human cardiac Troponin C and model peptides thereby exposing the differences between Cd(II) and Ca(II) binding to EF-hand proteins. The project will also explore subsequent protein interactions between HcTnC and TnI in the presence of Cd(II). This work will benefit students by allowing them to learn a multitude of techniques that will prepare them for careers in the pharmaceutical and biotechnology industries or make them very competitive for PhD programs. The project also has the possibility to provide Eastern North Carolina with highly skilled researchers thus positively impacting economic growth in the region. Most importantly, the data obtained from this project are highly likely to provide new insights into cadmium toxicity.