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Gene Review

SMF1  -  divalent metal ion transporter SMF1

Saccharomyces cerevisiae S288c

Synonyms: ESP1, Manganese transporter SMF1, YOL122C
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Disease relevance of SMF1


High impact information on SMF1

  • We propose that the Tre proteins specifically link Smf1 to the Bsd2-dependent quality control system [2].
  • The yeast manganese transporter Smf1 is subject to two levels of regulation: heavy metals induce its sequestration within the cell, and also its ubiquitination and degradation in the vacuole [2].
  • Their luminal domains are related to the transferrin receptor, but these are dispensable for Smf1 regulation [2].
  • Expression of Smf1p or the mammalian transporter DCT1 (Slc11a2) suppresses the above-mentioned phenotype [3].
  • This assumption was also tested by overexpressing the SMF1 gene in the temperature-sensitive mutant of the mitochondrial processing peptidase (MAS1) [4].

Biological context of SMF1

  • Wild-type and mutant variants of the Nramp1 and Nramp2 proteins were expressed in a yeast mutant bearing null alleles at the SMF1 and SMF2 loci, and complementation of the phenotypes of this yeast mutant was investigated [1].
  • We have recently shown that a member of the Nramp family of metal transporters, Saccharomyces cerevisiae Smf1p, is tightly regulated at the level of protein stability and protein sorting [5].
  • A model is proposed herein describing the probable role of Smf1 protein conformation in directing its movement to the vacuole versus cell surface in response to changes in metal ion availability [5].
  • Through promoter and protein-domain swapping experiments, we now demonstrate that the manganese regulation of Smf1p involves an internal protein-coding region that is separate from the N-terminal domain of this transporter [6].
  • Consistent with this, we found that increased sensitivity of yeast to EGTA in the high Na(+) medium is due to inhibition of SMF1- and SMF2-mediated metal ion transport by uncoupled Na(+) pathway [7].

Anatomical context of SMF1


Associations of SMF1 with chemical compounds

  • Although both SMF1- and SMF2-disrupted cells were very sensitive to EGTA, overexpression of BSD2 had little or no effect on sensitivity to EGTA [10].
  • SMF2-disrupted cells exhibited significantly greater resistance to adriamycin, whereas the resistance of SMF1-disrupted cells was only slightly improved [10].
  • The SMF1 gene codes for a highly hydrophobic protein and its deletion renders the yeast cells sensitive to low manganese concentration [4].
  • SMF1-mediated Fe(2+) transport exhibited saturation kinetics (K(m) = 2.2 microM), whereas the Na(+) flux did not, although both processes were electrogenic [7].
  • SMF1 is also permeable to Li(+), Rb(+), K(+), and Ca(2+), which likely share the same uncoupled pathway [7].

Regulatory relationships of SMF1

  • Hence, BSD2 prevents metal hyperaccumulation by exerting negative control over the SMF1 and SMF2 metal transport systems [8].

Other interactions of SMF1

  • Under these conditions, cells lacking both Pho84p and the high affinity Smf1p transporter accumulated low levels of manganese, although there was no major effect on activity of manganese-requiring enzymes [11].
  • In wild type strains, the bulk of Smf1p is normally directed to the vacuole and is rapidly degraded by vacuolar proteases in a PEP4-dependent manner [12].
  • Yeast Mn2+ transporter, Smf1p, is regulated by ubiquitin-dependent vacuolar protein sorting [13].
  • Epistasis studies show that these suppressors require functional Smf1p to alleviate the cdc1(Ts) growth defect, whereas Smf1p is dispensable for cdc1(Ts) suppression by a mutation (cos16/per1) that does not influence intracellular Mn(2+) levels [13].


  1. Functional complementation of the yeast divalent cation transporter family SMF by NRAMP2, a member of the mammalian natural resistance-associated macrophage protein family. Pinner, E., Gruenheid, S., Raymond, M., Gros, P. J. Biol. Chem. (1997) [Pubmed]
  2. Transferrin receptor-like proteins control the degradation of a yeast metal transporter. Stimpson, H.E., Lewis, M.J., Pelham, H.R. EMBO J. (2006) [Pubmed]
  3. The first external loop of the metal ion transporter DCT1 is involved in metal ion binding and specificity. Cohen, A., Nevo, Y., Nelson, N. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. A yeast manganese transporter related to the macrophage protein involved in conferring resistance to mycobacteria. Supek, F., Supekova, L., Nelson, H., Nelson, N. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  5. Mutational analysis of Saccharomyces cerevisiae Smf1p, a member of the Nramp family of metal transporters. Liu, X.F., Culotta, V.C. J. Mol. Biol. (1999) [Pubmed]
  6. The distinct methods by which manganese and iron regulate the Nramp transporters in yeast. Portnoy, M.E., Jensen, L.T., Culotta, V.C. Biochem. J. (2002) [Pubmed]
  7. Yeast SMF1 mediates H(+)-coupled iron uptake with concomitant uncoupled cation currents. Chen, X.Z., Peng, J.B., Cohen, A., Nelson, H., Nelson, N., Hediger, M.A. J. Biol. Chem. (1999) [Pubmed]
  8. Negative control of heavy metal uptake by the Saccharomyces cerevisiae BSD2 gene. Liu, X.F., Supek, F., Nelson, N., Culotta, V.C. J. Biol. Chem. (1997) [Pubmed]
  9. Two related genes encoding extremely hydrophobic proteins suppress a lethal mutation in the yeast mitochondrial processing enhancing protein. West, A.H., Clark, D.J., Martin, J., Neupert, W., Hartl, F.U., Horwich, A.L. J. Biol. Chem. (1992) [Pubmed]
  10. A novel role for Bsd2 in the resistance of yeast to adriamycin. Takahashi, T., Furuchi, T., Naganuma, A. J. Cell. Physiol. (2005) [Pubmed]
  11. The Saccharomyces cerevisiae high affinity phosphate transporter encoded by PHO84 also functions in manganese homeostasis. Jensen, L.T., Ajua-Alemanji, M., Culotta, V.C. J. Biol. Chem. (2003) [Pubmed]
  12. Post-translation control of Nramp metal transport in yeast. Role of metal ions and the BSD2 gene. Liu, X.F., Culotta, V.C. J. Biol. Chem. (1999) [Pubmed]
  13. Yeast Mn2+ transporter, Smf1p, is regulated by ubiquitin-dependent vacuolar protein sorting. Eguez, L., Chung, Y.S., Kuchibhatla, A., Paidhungat, M., Garrett, S. Genetics (2004) [Pubmed]
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