The Roles of PCBP1 and NCOA4 in Determining the Fate of Intracellular Ferritin

Iron is an essential micronutrient for virtually all forms of life, serving as a cofactor for enzymes involved in various metabolic pathways, including respiration, oxygen transport, electron transfer, DNA synthesis, and gene regulation. The proposed research aims at understanding the mechanisms and regulation of intracellular ferritin trafficking, a central component of the iron homeostasis machinery of the cell. Our multidisciplinary approach combines molecular biology, quantitative proteomics, protein biophysics, computational and structural biology, and leverages the complementary expertise of four collaborating laboratories in the US and Israel.

The proposed work will lead to the first biochemical, biophysical, structural, and cellular elucidation of previously uncharacterized NCOA4/PCBP1/ferritin interactions. It will (1) provide a mechanistic understanding of the pathways and fate of cellular ferritin trafficking at the molecular level, (2) answer long—standing questions of how ferritin iron homeostasis is programmed in biologically relevant contexts, and (3) establish the framework for understanding how ferritin biology is differentially controlled in different cell types to maintain both cellular and systemic iron homeostasis. Overall, our studies will provide a multiscale mechanistic understanding of the regulation of iron homeostasis and ferritin trafficking, both at the molecular and cellular levels, spanning protein—protein interactions, inter- organelle, intracellular, and the whole cell level.