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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-07-2108.
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Blood, 1 May 2003, Vol. 101, No. 9, pp. 3699-3707
RED CELLS
Iron transport by Nramp2/DMT1: pH regulation of
transport by 2 histidines in transmembrane domain 6
Steven Lam-Yuk-Tseung,
Gregory Govoni,
John Forbes, and
Philippe Gros
From the Department of Biochemistry, McGill Cancer
Center and Center for Host Resistance, McGill University,
Montreal, QC.
Mutations at natural resistance-associated macrophage protein 1 (Nramp1) impair phagocyte function and cause susceptibility to infections while mutations at Nramp2 (divalent metal
transporter 1 [DMT1]) affect iron homeostasis and cause severe
microcytic anemia. Structure-function relationships in the Nramp
superfamily were studied by mutagenesis, followed by functional
characterization in yeast and in mammalian cells. These studies
identify 3 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
(Gly185Arg) 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 (His267, His272) was identified in TM6. Surprisingly,
inactive His267 and His272 mutants could be rescued by lowering the pH
of the transport assay. This indicates that His267/His272 are not
directly involved in metal binding but, rather, play an important role
in pH regulation of metal transport by Nramp proteins.
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