Nramp: from sequence to structure and mechanism of divalent metal import

Abstract

Mn and Fe are important for energy metabolism and oxidative stress resistance and cells maintain adequate stores for survival and prevention of toxicity. Membrane permeases of the natural resistance-associated macrophage protein (Nramp) family importing protons and divalent metals are conserved from bacteria to man. Nramp hydrophobic core relates structurally to a superfamily of cation-driven carriers with inverted symmetry. Molecular phylogeny and sequence features support Nramp pseudo-symmetric three-dimensional (3D) model, and remote ancestry to the LeuT superfamily. Genetic analyses suggest conservation of Nramp sequence marks the transition from a phylogenetic out-group and may relate to divalent metal selectivity. Three phylogroups of bacterial proton-dependent manganese transporters (MntH) demonstrate specific patterns of sequence conservation suggesting functional constraints linked to ecological or taxonomical distributions, which may contribute to bacterial virulence. Nramp 3D model is supported experimentally by transmembrane topology and structure-function studies of Escherichia coli and mouse homologs as well as peptide structure analyses. Eukaryotic Nramps are required for Mn and Fe homeostasis, contributing in multicellular organisms to subcellular and systemic metal traffic and intercellular signaling. Nramps are subjected to elaborate regulation including developmental control of gene expression, protein subcellular targeting, dynamic metallo-dependent control of messenger RNA and protein stability and trafficking. Several human pathologies may result from defects in Nramp-dependent Fe(2+) or Mn(2+) transport, including iron overload, neurodegenerative diseases and innate susceptibility to infectious diseases.