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J. Biol. Chem., Vol. 282, Issue 49, 35646-35656, December 7, 2007

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Evolution of Differences in Transport Function in Slc11a Family Members^*

Michala Eichner Techau, Javier Valdez-Taubas¹, Jean-François Popoff, Richard Francis, Matthew Seaman², and Jenefer M. Blackwell²³

From the Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, University of Cambridge School of Clinical Medicine, Addenbrookes Hospital, Hills Road, Cambridge CB2 2XY and the MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, United Kingdom

Slc11a1 (formerly Nramp1) is a proton/divalent cation transporter that regulates cation homeostasis in macrophages. Slc11a2 mediates divalent cation uptake via the gut and delivery into cells. The mode of action of the two transporters remains controversial. Heterologous expression in frog oocytes shows Slc11a2 is a symporter, whereas Slc11a1 is an antiporter fluxing divalent cations against the proton gradient. This explains why Slc11a2, but not Slc11a1, can complement EGTA sensitivity in smf1/smf2/smf3 yeast. However, some studies of transport in mammalian cells suggest Slc11a1 is a symporter. We now demonstrate that Slc11a1, but not Slc11a2, complements a divalent cation stress phenotype in bsd2/rer1 yeast. This is the first description of a yeast complementation assay for Slc11a1 function. Given the prior demonstration in frog oocytes that Slc11a1 acts as an antiporter, the most plausible interpretation of the data is that Slc11a1 is rescuing bsd2/rer1 yeast by exporting divalent cations. Chimaeras define the N terminus, and a segment of the protein core preceding transmembrane domain 9 through transmembrane domain 12, as important in rescuing the divalent cation stress phenotype. EGTA sensitivity and divalent cation stress phenotypes in yeast expressing Slc11a orthologues show that symport activity is ancestral. Molecular changes that mediate rescue of the divalent cation stress phenotype post-date frogs and co-evolved with Slc11a1 orthologues that regulate divalent cation homeostasis in macrophages and resistance to infection in chickens and mammals.

Received for publication, August 22, 2007 , and in revised form, October 9, 2007.

^* This work was supported by The Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Fig. S1 and additional Results.

¹ Current address: Dept. Química Biológica (CIQUIBIC-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA, Córdoba, Argentina.

² Both authors contributed equally to the results of this work.

³ To whom correspondence should be addressed. Tel.: 44-1223-336947; Fax: 44-1223-331206; E-mail: jennie.blackwell{at}cimr.cam.ac.uk.

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