Computational Studies of the Dynamics of the Human Iron Exporter Ferroportin and Insight into the Role of Crucial Residues Involved in Pathogenic Mutations

Ferroportin (FPN/SLC40A1), the only known human iron exporter, plays a key role in iron homeostasis through an alternating access mechanism involving inward–open, occluded, and outward–open conformations. Pathogenic FPN mutations cause ferroportin–related iron overload, an autosomal dominant iron overload disease characterized by early–onset anemia, hepatic fibrosis, and diabetes. This disease can be further categorized into two subtypes: ferroportin disease, characterized by low transferrin saturation (TSAT) and iron overload predominantly in Kupffer cells, and ferroportin–related hemochromatosis, defined by high TSAT and iron overload in hepatocytes. However, the structural and functional characteristics governing FPN’s conformational transitions and their relationship to pathogenic mutations remain poorly understood. Therefore, we conducted comprehensive modeling and molecular dynamics studies to investigate the conformational states of the transporter and analyze the molecular basis of disease–causing mutations. Our analysis revealed shared dynamic properties across FPN conformations, with all the three main conformations displaying stable protein cores surrounded by dynamic peripheral regions. We observed significant differences in the most stable interactions established between the two lobes of the transporter across the three conformational states, enabling identification of key residues involved in state–dependent stabilization. These findings were interpreted in the context of known pathogenic mutations to assess their potential effects on protein stability and transport mechanism. This approach provides crucial insights into the molecular determinants of FPN function and dysfunction, offering a foundation for understanding how specific mutations disrupt its specific conformational states and lead to ferroportin–related iron overload. The identification of conformationally important residues enhances our understanding of FPN’s transport mechanism and provides a framework for interpreting the pathological consequences of genetic variants in iron metabolism disorders.