Pflügers Archiv

, Volume 447, Issue 5, pp 752–755 | Cite as

The SLC31 (Ctr) copper transporter family

The ABC of Solute Carriers Guest Editor: Matthias A. Hediger

Abstract

Copper is essential for many copper-dependent processes, including mitochondrial oxidative phosphorylation, free-radical detoxification, pigmentation, neurotransmitter synthesis, and iron metabolism. The identification of proteins for high affinity copper uptake and export has greatly expanded our understanding of cellular copper homeostasis. Copper export in human cells is mediated by the ATP7A and ATP7B P-type ATPases, which are, respectively, affected in the genetic disorders of copper metabolism, Menkes disease and Wilson disease. A different class of transporter known as the SLC31 or Ctr family of proteins mediates cellular copper uptake. These high-affinity copper transporters exist in all eukaryotes and their discovery has provided new insights into how cells acquire and regulate this essential nutrient. The following is a brief overview of the SLC31 copper transporter family with a focus on the human hCtr1 protein.

References

  1. 1.
    Harris ED (2000) Cellular copper transport and metabolism. Annu Rev Nutr 20:291–310Google Scholar
  2. 2.
    Dancis A, Haile D, Yuan DS, Klausner RD (1994) The Saccharomyces cerevisiae copper transport protein (Ctr1p). Biochemical characterization, regulation by copper, and physiologic role in copper uptake. J Biol Chem 269:25660–25667PubMedGoogle Scholar
  3. 3.
    Knight SA, Labbe S, Kwon LF, Kosman DJ, Thiele DJ (1996) A widespread transposable element masks expression of a yeast copper transport gene. Genes Dev 10:1917–1929PubMedGoogle Scholar
  4. 4.
    Klomp AE, Juijn JA, Van Der Gun LT, Van Den Berg IE, Berger R, Klomp LW (2003) The N-terminus of the human copper transporter 1 (hCTR1) is localized extracellularly, and interacts with itself. Biochem J 370:881–889Google Scholar
  5. 5.
    Zhou B, Gitschier J (1997) hCTR1: a human gene for copper uptake identified by complementation in yeast. Proc Natl Acad Sci USA 94:7481–7486CrossRefPubMedGoogle Scholar
  6. 6.
    Kampfenkel K, Kushnir S, Babiychuk E, Inze D, Van Montagu M (1995) Molecular characterization of a putative Arabidopsis thaliana copper transporter and its yeast homologue. J Biol Chem 270:28479–28486CrossRefPubMedGoogle Scholar
  7. 7.
    Lee J, Prohaska JR, Dagenais SL, Glover TW, Thiele DJ (2000) Isolation of a murine copper transporter gene, tissue specific expression and functional complementation of a yeast copper transport mutant. Gene 254:87–96CrossRefPubMedGoogle Scholar
  8. 8.
    Riggio M, Lee J, Scudiero R, Parisi E, Thiele DJ, Filosa S (2002) High affinity copper transport protein in the lizard Podarcis sicula: molecular cloning, functional characterization and expression in somatic tissues, follicular oocytes and eggs. Biochim Biophys Acta 1576:127–135CrossRefPubMedGoogle Scholar
  9. 9.
    Eisses JF, Kaplan JH (2002) Molecular characterization of hCTR1, the human copper uptake protein. J Biol Chem 277:29162–29171CrossRefPubMedGoogle Scholar
  10. 10.
    Puig S, Lee J, Lau M, Thiele DJ (2002) Biochemical and genetic analyses of yeast and human high affinity copper transporters suggest a conserved mechanism for copper uptake. J Biol Chem 277:26021–26030CrossRefPubMedGoogle Scholar
  11. 11.
    Pena MMO, Lee J, Thiele DJ (1999) A delicate balance: homeostatic control of copper uptake and distribution. J Nutr 129:1251–1260PubMedGoogle Scholar
  12. 12.
    Puig S, Thiele DJ (2002) Molecular mechanisms of copper uptake and distribution. Curr Opin Chem Biol 6:171–180CrossRefPubMedGoogle Scholar
  13. 13.
    Lee J, Pena MM, Nose Y, Thiele DJ (2002) Biochemical characterization of the human copper transporter Ctr1. J Biol Chem 277:4380–4387PubMedGoogle Scholar
  14. 14.
    Klomp AE, Tops BB, Van Denberg IE, Berger R, Klomp LW (2002) Biochemical characterization and subcellular localization of human copper transporter 1 (hCTR1). Biochem J 364:497–505CrossRefPubMedGoogle Scholar
  15. 15.
    Pena MM, Puig S, Thiele DJ (2000) Characterization of the Saccharomyces cerevisiae high-affinity copper transporter Ctr3. J Biol Chem 275:33244–33251CrossRefPubMedGoogle Scholar
  16. 16.
    Portnoy ME, Schmidt PJ, Rogers RS, Culotta VC (2001) Metal transporters that contribute copper to metallochaperones in Saccharomyces cerevisiae. Mol Genet Genome 265:873–882CrossRefGoogle Scholar
  17. 17.
    Bellemare DR, Shaner L, Morano KA, Beaudoin J, Langlois R, Labbe S (2002) Ctr6, a vacuolar membrane copper transporter in Schizosaccharomyces pombe. J Biol Chem 277:46676–46686CrossRefPubMedGoogle Scholar
  18. 18.
    Kuo YM, Zhou B, Cosco D, Gitschier J (2001) The copper transporter CTR1 provides an essential function in mammalian embryonic development. Proc Natl Acad Sci USA 98:6836–6841CrossRefPubMedGoogle Scholar
  19. 19.
    Lee J, Prohaska JR, Thiele DJ (2001) Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development. Proc Natl Acad Sci USA 98:6842–6847CrossRefPubMedGoogle Scholar
  20. 20.
    Lee J, Petris MJ, Thiele DJ (2002) Characterization of mouse embryonic cells deficient in the Ctr1 high-affinity copper transporter. Identification of a Ctr1-independent copper transport system. J Biol Chem 277:40253–40259CrossRefPubMedGoogle Scholar
  21. 21.
    Huffman DL, O'Halloran TV (2001) Function, structure, and mechanism of intracellular copper trafficking proteins. Annu Rev Biochem 70:677–701Google Scholar
  22. 22.
    Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC (1998) Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA 95:1148–1153CrossRefPubMedGoogle Scholar
  23. 23.
    Fleming MD, Trenor CC III, Su MA, Foernzler D, Beier DR, Dietrich WF, Andrews NC (1997) Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 16:383–386PubMedGoogle Scholar
  24. 24.
    Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388:482–488CrossRefPubMedGoogle Scholar
  25. 25.
    Petris MJ, Smith K, Lee J, Thiele DJ (2003) Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1. J Biol Chem 278:9639–9646CrossRefPubMedGoogle Scholar
  26. 26.
    Ooi CE, Rabinowich E, Dancis A, Bonifacino JS, Klausner RD (1996) Copper-dependent degradation of the Saccharomyces cerevisiae plasma membrane copper transporter Ctr1p in the apparent absence of endocytosis. EMBO J 15:3515–3523PubMedGoogle Scholar
  27. 27.
    Sullivan AL, Grasso JA, Weintraub LR (1976) Micropinocytosis of transferrin by developing red cells: an electron-microscopic study utilizing ferritin-conjugated transferrin and ferritin-conjugated antibodies to transferrin. Blood 47:133–143PubMedGoogle Scholar

Copyright information

© Springer-Verlag  2004

Authors and Affiliations

  1. 1.Department of Nutritional SciencesUniversity of Missouri-ColumbiaColumbiaUSA

Personalised recommendations