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. 2017 Nov;24(4):462-467.
doi: 10.1016/j.tracli.2017.07.002. Epub 2017 Aug 18.

Deciphering the Molecular Basis of Ferroportin Resistance to Hepcidin: Structure/function Analysis of Rare SLC40A1 Missense Mutations Found in Suspected Hemochromatosis Type 4 Patients

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Deciphering the Molecular Basis of Ferroportin Resistance to Hepcidin: Structure/function Analysis of Rare SLC40A1 Missense Mutations Found in Suspected Hemochromatosis Type 4 Patients

M Le Tertre et al. Transfus Clin Biol. .

Abstract

Genetic medicine applied to the study of hemochromatosis has identified the systemic loop controlling iron homeostasis, centered on hepcidin-ferroportin interaction. Current challenges are to dissect the molecular pathways underlying liver hepcidin synthesis in response to circulatory iron, HFE, TFR2, HJV, TMPRSS6 and BMP6 functions, and to define the major structural elements of hepcidin-ferroportin interaction. We built a first 3D model of human ferroportin structure, using the crystal structure of EmrD, a bacterial drug efflux transporter of the Major Facilitator Superfamily, as template. The model enabled study of disease-associated mutations, and guided mutagenesis experiments to determine the role of conserved residues in protein stability and iron transport. Results revealed novel amino acids that are critical for the iron export function and the hepcidin-mediated inhibition mechanism: for example, tryptophan 42, localized in the extracellular end of the ferroportin pore and involved in both biological functions. Here, we propose a strategy that is not limited to structure analysis, but integrates information from different sources, including human disease-associated mutations and functional in vitro assays. The first major hypothesis of this PhD thesis is that ferroportin resistance to hepcidin relies on different molecular mechanisms that are critical for ferroportin endocytosis, and include at least three fundamental steps: (i) hepcidin binding to ferroportin, (ii) structural reorganization of the N- and C-ter ferroportin lobes, and (iii) ferroportin ubiquitination.

Keywords: Ferroportin; Ferroportine; Gain-of-function mutations; Hemochromatosis; Hepcidin; Hepcidine; Hémochromatose; Iron metabolism; Mutations « gain-de-fonction »; Métabolisme du fer.

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