Schematic representation of mouse Nramp2 (DMT1) isoform II (−IRE) and isoform I (+IRE).

The 12 transmembrane domains are predicted from hydropathy profiling, calculations of hydrophobic moment, and other computer-assisted analyses6 and from direct epitope mapping studies.13 Individual predicted intracellular and extracellular segments are identified, and their position within the primary sequence is shown. Amino acid residues defining sequence landmarks and signature motifs are depicted in different colors, including negatively and positively charged residues within predicted TM domains (dark blue), conserved histidine residues in TM6 (red), glycine residues in TM4 altered in anemicmk/Belgrade mutants (Gly185Arg), and mutated (inNramp1) in mice susceptible to infections (Gly184Asp) (yellow). Also identified are Asn-linked glycosylation signals in the TM7-TM8 extracytoplasmic loop (black), predicted membrane targeting/sorting motifs (tyrosine-based and dileucine) (green), and consensus transport signature common to Nramp orthologs and present in the cytoplasmic face of membrane anchors of bacterial periplasmic permeases (orange). The 2 different C-termini of the protein generated by alternative mRNA splicing containing or not an iron-response element (isoform I, +IRE; isoform II, −IRE) in the 3′ untranslated region are identified, with corresponding numbering. Finally, the polarity of the protein and membrane domains with respect to the membrane (light blue) is indicated (in, out, lumen).