The C282Y mutation in hereditary hemochromatosis: structural and functional implications investigated by molecular dynamics simulations

Hereditary hemochromatosis (HH) is an autosomal recessive disease characterized by an improper regulation of iron uptake, leading to an iron overload in different specific organs. The responsible of HH is a mutated protein called HFE, a class I major histocompatibility complex (MHC) homolog, formed by two domains: the 1,2 MHC-like domain and the 3 immunoglobulin-like domain. 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 that prevents its externalization at the cell surface. wt HFE competes with iron-loaded transferrin (Tf) for binding to the transferrin receptor (TfR) at the cell surface. HFE interferes with Tf binding site on TfR and regulates iron absorption. The mutated protein is not able to bind TfR and the regulation fails, causing the iron overload. In this work, we tried to give insight into the effects of C282Y (C260Y) mutation on the HFE structure and on its interaction with the 2m domain, by means of molecular dynamics simulation technique. We followed the evolution of four systems: the HFE-2m complex and the HFE chain alone, in the wt and mutated form, accelerating the structural changes by means of a temperature increment. The mutated tyrosine comes to be in a hydrophobic environment and try to move towards a more polar one enlarging the barrel, helped in this by the broken disulphide bond. Its partial exposition to the solvent perturbs the molecular surface, affecting the interaction with the 2m domain and of the latter with the MHC-like one. The main effect is the exposition of Trp60 residue of 2m, known to be fundamental for the association of beta2m with HFE chain.