Effects of C282Y mutation in HFE protein structure and interactions, investigated by MD simulations: implication in hereditary hemochromatosis

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, formed by two domains: the 1,2 MHC-like domain and the 3 immunoglobulin-like domain.1 Wilde type 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.2 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, preventing its externalization at the cell surface and its binding with TfR.3 In this work, we investigated the effects of C282Y (C260Y in the mature protein) 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 the HFE-2m complex 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 tries to move towards a more polar one enlarging the barrel, helped in this by the broken disulphide bond. PCA analysis allows to investigate how the reciprocal interactions of 3, 2m and MHC domains are affected by these conformational changes. Many conserved contacts are lost, but the main effect is the exposition of Trp60 residue of 2m, known to be fundamental for the association of 2m with the HFE chain.