Insights in Interactions Reshaping Caused by the HFE Protein C282Y Mutation in Hereditary Hemochromatosis

HFE protein is a class I major histocompatibility complex (MHC) homolog, formed by two domains: the 1,2 MHC-like domain and the 3 immunoglobulin-like domain. WT HFE competes with iron-loaded transferrin (Tf) for binding to the transferrin receptor (TfR) at the cell surface and, interfering with Tf binding site on TfR, regulates iron absorption. The mutated protein is not able to bind TfR and the regulation fails, causing an iron overload, a characteristic of Hereditary Hemochromatosis (HH) desease. The predominant mutation in HH is the C282Y (C260Y in the mature protein) in the 3 domain, which converts a cysteine residue in a tyrosine, breaking a disulphide bond and affecting the association of HFE with a 2-microglobulin (2m) chain, therefore preventing its externalization at the cell surface. Several hypothesis were made about this failing. By means of molecular dynamics simulations, we try to go into detail of structural changes occurring in the 3 domain due to the mutation, which alter the electrostatic features of protein surfaces affecting the interaction with the 2m chain and with the 1,2 domain of HFE itself. PCA analysis allowed to observe a reciprocal rotation of the three domains, which leads to the loss of several conserved contacts, but substantially maintains the overall fold of each of them.