Open Access Dissertation
Date of Award
Biochemistry and Molecular Biology
Timothy L. Stemmler
Brian F. Edwards
Biological Role of Ferritin - Iron is essential for life and often utilized as a cofactor in many proteins. In humans, iron accumulation causes cirrhosis, arthritis, cardiomyopathy and diabetes mellitus, and it is associated with increased risk of cancer and heart disease. In contrast, decreased brain iron content results in permanent neurocognitive and motor impairment. Intracellular iron content must be maintained within a narrow range to avoid the adverse effects of iron depletion or excess, and this function is performed by the protein ferritin. Ferritins are iron storage proteins that are ubiquitously expressed in animals, plants and bacteria. They serve both to sequester excess iron taken up by the cell and to release stored iron to meet the cell's metabolic needs during iron scarcity. Ferritin's capacity to store iron is therefore essential for life.
PCBP1 is an iron chaperone to ferritin - This work shows that human Poly r(C)-Binding Protein family are essential for ferritin iron loading. In vivo, depletion of PCBP1 inhibits ferritin loading and increases cytosolic iron pools. In vitro, PCBPs bind iron with an affinity similar to other metallochaperones. Based on these data, we believe that the PCBPs are functional iron chaperones that deliver iron to ferritin, hence promoting maintenance of cellular iron homeostasis. The objective is to characterize the molecular details of the interaction between PCBPs, iron and ferritin using biophysical tools such as X-ray absorption spectroscopy, Mossbauer spectroscopy and Isothermal Titration Calorimetry. This work will help elucidate key events that lead to iron uptake/absorption in the body and in the general regulation of iron homeostasis in humans. It will also lead to improved treatment strategies for disorders related to cellular iron imbalance and heart disease.
Subramanian, Poorna, "Elucidation Of The Functional Role Of Pcbp-The Cytosolic Iron Chaperone Protein Family, In Cellular Iron Homeostasis" (2013). Wayne State University Dissertations. 704.