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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-07-2108.
Submitted July 15, 2002
Accepted December 19, 2002
Iron transport by NRAMP2/DMT1: pH regulation of transport by two histidines in transmembrane domain 6
Steven Lam-Yuk-Tseung, Gregory Govoni, John Forbes, and Philippe Gros*
Department of Biochemistry, McGill University, Montreal, PQ, Canada
* Corresponding author; email: gros{at}med.mcgill.ca.
Mutations at Nramp1 impair phagocyte function and cause susceptibility to infections while mutations at Nramp2 (DMT1) affect iron homeostasis and cause severe microcytic anemia. Structure-function relationships in the Nramp super family were studied by mutagenesis, followed by functional characterization in yeast and in mammalian cells. These studies identify three negatively charged and highly conserved residues in transmembrane domains (TM) 1, 4, and 7 as essential for cation transport by Nramp2/DMT1. The introduction of a charged residue (G185R) in TM4 found in the naturally-occurring microcytic anemia mk (mouse) and Belgrade (rat) mutants is shown to cause a partial or complete loss of function in mammalian and yeast cells, respectively. A pair of mutation-sensitive and highly conserved histidines (H267, H272) was identified in TM6. Surprisingly, inactive H267 and H272 mutants could be rescued by lowering the pH of the transport assay. This indicates that H267/H272 are not directly involved in metal binding but rather they play an important role in pH regulation of metal transport by Nramp proteins.
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