The HFE protein C282Y mutation in Hereditary Hemochromatosis: effects on structural reshaping and surface pattern alteration

HFE is a protein involved in the regulation of iron uptake, by competing with iron-loaded transferrin for binding to the transferrin receptor (TfR) at the cell surface. It is formed by two domains: the alpha1,2 MHC-like domain and the alpha3 immunoglobulin-like domain. In Hereditary Hemochromatosis (HH), the mutated protein is no longer able to bind TfR and the regulation fails, causing an iron overload. The predominant mutation in HH is the C282Y in the alpha3 domain, which somehow affects the association of HFE with a beta2-microglobulin chain, preventing its externalization at the cell surface, and, consequently, the binding to TfR. By means of molecular dynamics simulations, we investigated the structural changes occurring in the proteins as a result of the mutation, unraveling the alterations in the mutual interactions of the three domains. The mutated tyrosine tends to expose to the solvent, enlarging the beta structure of the alpha3 domain and causing the displacement of several hydrophobic residues. The distribution and extent of hydrophobic patches on the protein surface is altered, suggesting a higher aggregation propensity. PCA analysis allowed to observe the reciprocal rotation of the three domains, which leads to the loss of several conserved contacts, evolving towards an unstable structure but substantially maintaining the overall fold of each individual domain.