The Structural Basis of Iron Sensing by the Human F-box Protein FBXL5

Iron is an essential chemical element for all forms of life. It serves as a cofactor for many proteins and enzymes involved in oxygen transport, energy metabolism and DNA synthesis[1, 2]. Mammalian cells need to maintain a sufficient amount of iron to support the synthesis of proteins that require iron as a co-factor. Iron is imported into the cells through the circulating iron transporter transferrin[3, 4]. Iron-loaded transferrin binds to cell surface transferrin receptor, resulting in the endocytosis of transferrin and delivery of the iron cargo into the cells[4]. Excess iron in the cells is stored in the cytosolic protein ferritin[4]. Iron regulatory proteins IRP1 and IRP2 maintain the homeostasis of iron through post-translational regulation of the expression of transferrin receptor and ferritin[2, 5]. In iron-replete cells IRP2 is ubiquitinated and degraded by the proteasome. The F-box and leucine-rich repeat containing protein FBXL5 serves as a cytosolic iron sensor that regulates the ubiquitination of IRP2 by the SKP1-CUL1-FBXL5 (SCF) E3 ubiquitin ligase complex[6, 7]. FBXL5 also plays critical roles in sensing oxygen in the cytosol[6, 7]. Knock out of FBXL5 in mice result in embryonic mortality due to excess accumulation of iron[8].