Cryptococcus neoformans is an important human opportunistic pathogen and a facultative intracellular parasite, particularly in HIV-infected individuals. Little is known about metal ion transport in this organism. C. neoformans encodes a single member of the Nramp (natural resistance-associated macrophage protein) family of bivalent cation transporters, known as Cramp, which we have cloned and expressed in Xenopus laevis oocytes and Spodoptera frugiperda Sf 21 insect cells. Cramp induces saturable transport of a broad range of bivalent transition series cations, including Mn2+, Fe2+, Co2+ and Ni2+. Maximal cation transport occurs at pH 5.5–6.0, consistent with the proton gradient-based energetics of other Nramp orthologues. Mn2+ transport is diminished in the presence of 140 mM Na+, compatible with a Na+ slippage mechanism proposed for the Saccharomyces cerevisiae Nramp orthologue Smf1p. Cramp resembles Smf1p with respect to predicted membrane topology, substrate specificity and pH dependence, but differs in terms of its apparent affinity for Mn2+ and negligible inhibition by Zn2+. Cramp is the first Nramp orthologue from a fungal pathogen to be functionally characterized. Insights afforded by these findings will allow the formulation of new hypotheses regarding the role of metal ions in the pathophysiology of cryptococcosis.
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Research Article|
December 14 2004
The Nramp orthologue of Cryptococcus neoformans is a pH-dependent transporter of manganese, iron, cobalt and nickel
Daniel AGRANOFF;
Daniel AGRANOFF
1
*Department of Cellular and Molecular Medicine (Infectious Diseases), St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, U.K.
1To whom correspondence should be addressed (email dagranof@sghms.ac.uk).
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Lauren COLLINS;
Lauren COLLINS
*Department of Cellular and Molecular Medicine (Infectious Diseases), St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, U.K.
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David KEHRES;
David KEHRES
†Department of Pharmacology, Case School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4965, U.S.A.
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Tom HARRISON;
Tom HARRISON
*Department of Cellular and Molecular Medicine (Infectious Diseases), St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, U.K.
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Michael MAGUIRE;
Michael MAGUIRE
†Department of Pharmacology, Case School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4965, U.S.A.
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Sanjeev KRISHNA
Sanjeev KRISHNA
*Department of Cellular and Molecular Medicine (Infectious Diseases), St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, U.K.
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Publisher: Portland Press Ltd
Received:
April 20 2004
Revision Received:
August 09 2004
Accepted:
September 07 2004
Accepted Manuscript online:
September 07 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 385 (1): 225–232.
Article history
Received:
April 20 2004
Revision Received:
August 09 2004
Accepted:
September 07 2004
Accepted Manuscript online:
September 07 2004
Citation
Daniel AGRANOFF, Lauren COLLINS, David KEHRES, Tom HARRISON, Michael MAGUIRE, Sanjeev KRISHNA; The Nramp orthologue of Cryptococcus neoformans is a pH-dependent transporter of manganese, iron, cobalt and nickel. Biochem J 1 January 2005; 385 (1): 225–232. doi: https://doi.org/10.1042/BJ20040836
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