UCLA

Iron is an essential micronutrient required for hemoglobin synthesis and for the maturation of red blood cells in the bone marrow. Disorders of iron delivery cause both anemia and iron-overload toxicities, depending on the nature of the condition. Erythroferrone (ERFE) is a marrow-derived hormone that coordinates the availability of iron for developing erythrocytes. ERFE acts by suppressing hepatic production of the iron regulator hepcidin, thereby making iron from body stores and from the diet accessible for use by erythroblasts. Suppression of hepcidin by ERFE is thought to be mediated by the sequestration of bone morphogenetic proteins (BMPs) that function through the SMAD pathway to activate hepcidin transcription, but further mechanistic details are poorly understood. Here, we present a systematic structure-function study of ERFE, elucidating how its structural domains enable its important biological function. We identify multiple conserved domains of the protein and use biophysical, biochemical, and computational modeling techniques to explain the interaction between ERFE and BMPs, thereby illuminating its noteworthy mechanism of action.