A 3-dimensional model building by homology of the HFE protein: molecular consequences and application to antibody development

Genetic hemochromatosis (GH) is a common inherited disease of iron metaboli sm affecting 2-5 in 1000 individuals of European origin. A candidate gene f or GK, namely HFE has been recently characterized. Structural studies of th e protein product of the HFE gene are of major interest for a better unders tanding of the molecular physiopathology in iron overload. We have built a 3-dimensional model of the HFE protein based on congruent to 40% homology o f sequence identity with HLA-Aw68, another MHC class I molecule. This work presents the first 3-dimensional structure of HFE available in the public d omain (http://swift.embl-heidelberg.de/service/francois). The 3-dimensional characteristics of the protein complexed with the beta 2-microglobulin are presented. The model has been used to predict immunogenic loops and to dev elop an antibody able to recognize a protein exhibiting the same molecular weight as HFE. Structural consequences of two common mutations are debated and evolutionary hypotheses are considered in the discussion of the particu lar biological activity of HFE. This study shows that a strategy based on h omology modeling is sufficient to undertake biological investigations. (C) 2000 Elsevier Science B.V. All rights reserved.