Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mechanisms for copper acquisition, distribution and regulation

Abstract

Copper (Cu) is a redox-active metal ion essential for most aerobic organisms. Cu serves as a catalytic and structural cofactor for enzymes that function in energy generation, iron acquisition, oxygen transport, cellular metabolism, peptide hormone maturation, blood clotting, signal transduction and a host of other processes. The inability to control Cu balance is associated with genetic diseases of overload and deficiency and has recently been tied to neurodegenerative disorders and fungal virulence. The essential nature of Cu, the existence of human genetic disorders of Cu metabolism and the potential impact of Cu deposition in the environment have been driving forces for detailed investigations in microbial and eukaryotic model systems. Here we review recent advances in the identification and function of cellular and systemic molecules that drive Cu accumulation, distribution and sensing.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Model for intestinal Cu absorption and peripheral distribution.
Figure 2: Structural model for the Ctr1 Cu1+ channel.
Figure 3: Cu import, intracellular routing and biliary secretion in the liver.
Figure 4: Cu loading of mitochondrial cytochrome oxidase.
Figure 5: Cu1+ delivery to P-type ATPases that mediate Cu excretion in the bile and Cu passage into the lumen of the secretory apparatus.
Figure 6: Copper insertion into Cu/Zn SOD by the CCS Cu chaperone.
Figure 7: Model for the intersection of Cu homeostasis with fungal virulence in the human pathogen C. neoformans.

References

  1. Linder, M.C. & Goode, C.A. Biochemistry of Copper 1–413 (Springer-Verlag New York, LLC, New York, 1991).

    Google Scholar 

  2. Bertini, I., Gray, H.B., Stiefel, E. & Valentine, J.S. Biological Inorganic Chemistry 1–712 (Sausalito, California, USA, 2007).

    Google Scholar 

  3. Lippard, S.J. & Berg, J.M. Principles of Bioinorganic Chemistry 3–388 (University Science Books, Mill Valley, California, USA, 1994).

    Google Scholar 

  4. Andreini, C., Banci, L., Bertini, I. & Rosato, A. Occurrence of copper proteins through the three domains of life: a bioinformatic approach. J. Proteome Res. 7, 209–216 (2008).

    CAS  PubMed  Google Scholar 

  5. Hellman, N.E. & Gitlin, J.D. Ceruloplasmin metabolism and function. Annu. Rev. Nutr. 22, 439–458 (2002).

    CAS  PubMed  Google Scholar 

  6. Harris, Z.L., Durley, A.P., Man, T.K. & Gitlin, J.D. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc. Natl. Acad. Sci. USA 96, 10812–10817 (1999).

    CAS  PubMed  Google Scholar 

  7. Madsen, E. & Gitlin, J.D. Copper and iron disorders of the brain. Annu. Rev. Neurosci. 30, 317–337 (2007).

    CAS  PubMed  Google Scholar 

  8. Adlard, P.A. & Bush, A.I. Metals and Alzheimer's disease. J. Alzheimers Dis. 10, 145–163 (2006).

    PubMed  Google Scholar 

  9. Strozyk, D. et al. Zinc and copper modulate Alzheimer Aβ levels in human cerebrospinal fluid. Neurobiol. Aging published online, doi:10:1016/j.neurobiolaging.2007.10.012 (10 December 2007).

    Google Scholar 

  10. Bharathi, Indi, S.S. & Rao, K.S. Copper- and iron-induced differential fibril formation in alpha-synuclein: TEM study. Neurosci. Lett. 424, 78–82 (2007).

    PubMed  Google Scholar 

  11. Jones, C.E., Abdelraheim, S.R., Brown, D.R. & Viles, J.H. Preferential Cu2+ coordination by His96 and His111 induces beta-sheet formation in the unstructured amyloidogenic region of the prion protein. J. Biol. Chem. 279, 32018–32027 (2004).

    CAS  PubMed  Google Scholar 

  12. Nose, Y., Rees, E.M. & Thiele, D.J. Structure of the Ctr1 copper trans'PORE'ter reveals novel architecture. Trends Biochem. Sci. 31, 604–607 (2006).

    CAS  PubMed  Google Scholar 

  13. Puig, S. & Thiele, D.J. Molecular mechanisms of copper uptake and distribution. Curr. Opin. Chem. Biol. 6, 171–180 (2002).

    CAS  PubMed  Google Scholar 

  14. Maryon, E.B., Molloy, S.A., Zimnicka, A.M. & Kaplan, J.H. Copper entry into human cells: progress and unanswered questions. Biometals 20, 355–364 (2007).

    CAS  PubMed  Google Scholar 

  15. Puig, S., Lee, J., Lau, M. & Thiele, D.J. Biochemical and genetic analyses of yeast and human high affinity copper transporters suggest a conserved mechanism for copper uptake. J. Biol. Chem. 277, 26021–26030 (2002).

    CAS  PubMed  Google Scholar 

  16. Nose, Y., Kim, B.E. & Thiele, D.J. Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab. 4, 235–244 (2006).

    CAS  PubMed  Google Scholar 

  17. Dancis, A. et al. Molecular characterization of a copper transport protein in S. cerevisiae: an unexpected role for copper in iron transport. Cell 76, 393–402 (1994).

    CAS  PubMed  Google Scholar 

  18. Pena, M.M., Puig, S. & Thiele, D.J. Characterization of the Saccharomyces cerevisiae high affinity copper transporter Ctr3. J. Biol. Chem. 275, 33244–33251 (2000).

    CAS  PubMed  Google Scholar 

  19. Aller, S.G. & Unger, V.M. Projection structure of the human copper transporter CTR1 at 6-A resolution reveals a compact trimer with a novel channel-like architecture. Proc. Natl. Acad. Sci. USA 103, 3627–3632 (2006).

    CAS  PubMed  Google Scholar 

  20. Rees, E.M. & Thiele, D.J. Identification of a vacuole-associated metalloreductase and its role in Ctr2-mediated intracellular copper mobilization. J. Biol. Chem. 282, 21629–21638 (2007).

    CAS  PubMed  Google Scholar 

  21. Lee, J., Petris, M.J. & Thiele, D.J. 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, 40253–40259 (2002).

    CAS  PubMed  Google Scholar 

  22. Ohgami, R.S., Campagna, D.R., McDonald, A. & Fleming, M.D. The Steap proteins are metalloreductases. Blood 108, 1388–1394 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. McKie, A.T. et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291, 1755–1759 (2001).

    CAS  PubMed  Google Scholar 

  24. Petris, M.J., Smith, K., Lee, J. & Thiele, D.J. Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1. J. Biol. Chem. 278, 9639–9646 (2003).

    CAS  PubMed  Google Scholar 

  25. Klomp, A.E., Tops, B.B., Van Denberg, I.E., Berger, R. & Klomp, L.W. Biochemical characterization and subcellular localization of human copper transporter 1 (hCTR1). Biochem. J. 364, 497–505 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kuo, Y.M., Gybina, A.A., Pyatskowit, J.W., Gitschier, J. & Prohaska, J.R. Copper transport protein (Ctr1) levels in mice are tissue specific and dependent on copper status. J. Nutr. 136, 21–26 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Guo, Y., Smith, K., Lee, J., Thiele, D.J. & Petris, M.J. Identification of methionine-rich clusters that regulate copper-stimulated endocytosis of the human Ctr1 copper transporter. J. Biol. Chem. 279, 17428–17433 (2004).

    CAS  PubMed  Google Scholar 

  28. Fleming, M.D. et al. 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, 1148–1153 (1998).

    CAS  PubMed  Google Scholar 

  29. Zimnicka, A.M., Maryon, E.B. & Kaplan, J.H. Human copper transporter hCTR1 mediates basolateral uptake of copper into enterocytes: implications for copper homeostasis. J. Biol. Chem. 282, 26471–26480 (2007).

    CAS  PubMed  Google Scholar 

  30. Lee, J., Prohaska, J.R. & Thiele, D.J. Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development. Proc. Natl. Acad. Sci. USA 98, 6842–6847 (2001).

    CAS  PubMed  Google Scholar 

  31. Kuo, Y.M., Zhou, B., Cosco, D. & Gitschier, J. The copper transporter CTR1 provides an essential function in mammalian embryonic development. Proc. Natl. Acad. Sci. USA 98, 6836–6841 (2001).

    CAS  PubMed  Google Scholar 

  32. Portnoy, M.E., Schmidt, P.J., Rogers, R.S. & Culotta, V.C. Metal transporters that contribute copper to metallochaperones in Saccharomyces cerevisiae. Mol. Genet. Genomics 265, 873–882 (2001).

    CAS  PubMed  Google Scholar 

  33. Rees, E.M., Lee, J. & Thiele, D.J. Mobilization of intracellular copper stores by the ctr2 vacuolar copper transporter. J. Biol. Chem. 279, 54221–54229 (2004).

    CAS  PubMed  Google Scholar 

  34. Bellemare, D.R. et al. Ctr6, a vacuolar membrane copper transporter in Schizosaccharomyces pombe. J. Biol. Chem. 277, 46676–46686 (2002).

    CAS  PubMed  Google Scholar 

  35. Kampfenkel, K., Kushnir, S., Babiychuk, E., Inze, D. & Van Montagu, M. Molecular characterization of a putative Arabidopsis thaliana copper transporter and its yeast homologue. J. Biol. Chem. 270, 28479–28486 (1995).

    CAS  PubMed  Google Scholar 

  36. Zhou, B. & Gitschier, J. hCTR1: a human gene for copper uptake identified by complementation in yeast. Proc. Natl. Acad. Sci. USA 94, 7481–7486 (1997).

    CAS  PubMed  Google Scholar 

  37. van den Berghe, P.V. et al. Human copper transporter 2 is localized in late endosomes and lysosomes and facilitates cellular copper uptake. Biochem. J. 407, 49–59 (2007).

    CAS  PubMed  Google Scholar 

  38. Bertinato, J., Swist, E., Plouffe, L.J., Brooks, S.P. & L'Abbé, M.R. Ctr2 is partially localized to the plasma membrane and stimulates copper uptake in COS-7 cells. Biochem. J. 409, 731–740 (2008).

    CAS  PubMed  Google Scholar 

  39. Cobine, P.A., Ojeda, L.D., Rigby, K.M. & Winge, D.R. Yeast contain a non-proteinaceous pool of copper in the mitochondrial matrix. J. Biol. Chem. 279, 14447–14455 (2004).

    CAS  PubMed  Google Scholar 

  40. Glerum, D.M., Shtanko, A. & Tzagoloff, A. Characterization of COX17, a yeast gene involved in copper metabolism and assembly of cytochrome oxidase. J. Biol. Chem. 271, 14504–14509 (1996).

    CAS  PubMed  Google Scholar 

  41. Abajian, C., Yatsunyk, L.A., Ramirez, B.E. & Rosenzweig, A.C. Yeast cox17 solution structure and copper(I) binding. J. Biol. Chem. 279, 53584–53592 (2004).

    CAS  PubMed  Google Scholar 

  42. Arnesano, F., Balatri, E., Banci, L., Bertini, I. & Winge, D.R. Folding studies of Cox17 reveal an important interplay of cysteine oxidation and copper binding. Structure 13, 713–722 (2005).

    CAS  PubMed  Google Scholar 

  43. Cobine, P.A., Pierrel, F., Bestwick, M.L. & Winge, D.R. Mitochondrial matrix copper complex used in metallation of cytochrome oxidase and superoxide dismutase. J. Biol. Chem. 281, 36552–36559 (2006).

    CAS  PubMed  Google Scholar 

  44. Horng, Y.C., Cobine, P.A., Maxfield, A.B., Carr, H.S. & Winge, D.R. Specific copper transfer from the Cox17 metallochaperone to both Sco1 and Cox11 in the assembly of yeast cytochrome C oxidase. J. Biol. Chem. 279, 35334–35340 (2004).

    CAS  PubMed  Google Scholar 

  45. Leary, S.C. et al. Human SCO1 and SCO2 have independent, cooperative functions in copper delivery to cytochrome c oxidase. Hum. Mol. Genet. 13, 1839–1848 (2004).

    CAS  PubMed  Google Scholar 

  46. Rigby, K., Zhang, L., Cobine, P.A., George, G.N. & Winge, D.R. characterization of the cytochrome c oxidase assembly factor Cox19 of Saccharomyces cerevisiae. J. Biol. Chem. 282, 10233–10242 (2007).

    CAS  PubMed  Google Scholar 

  47. Cobine, P.A., Pierrel, F. & Winge, D.R. Copper trafficking to the mitochondrion and assembly of copper metalloenzymes. Biochim. Biophys. Acta 1763, 759–772 (2006).

    CAS  PubMed  Google Scholar 

  48. Wernimont, A.K., Huffman, D.L., Lamb, A.L., O'Halloran, T.V. & Rosenzweig, A.C. Structural basis for copper transfer by the metallochaperone for the Menkes/Wilson disease proteins. Nat. Struct. Biol. 7, 766–771 (2000).

    CAS  PubMed  Google Scholar 

  49. Anastassopoulou, I. et al. Solution structure of the apo and copper(I)-loaded human metallochaperone HAH1. Biochemistry 43, 13046–13053 (2004).

    CAS  PubMed  Google Scholar 

  50. Pufahl, R.A. et al. Metal ion chaperone function of the soluble Cu(I) receptor Atx1. Science 278, 853–856 (1997).

    CAS  PubMed  Google Scholar 

  51. Banci, L., Bertini, I., Chasapis, C.T., Rosato, A. & Tenori, L. Interaction of the two soluble metal-binding domains of yeast Ccc2 with copper(I)-Atx1. Biochem. Biophys. Res. Commun. 364, 645–649 (2007).

    CAS  PubMed  Google Scholar 

  52. Lutsenko, S., LeShane, E.S. & Shinde, U. Biochemical basis of regulation of human copper-transporting ATPases. Arch. Biochem. Biophys. 463, 134–148 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Linz, R. et al. Intracellular targeting of copper-transporting ATPase ATP7A in a normal and Atp7b−/− kidney. Am. J. Physiol. Renal Physiol. 294, F53–F61 (2008).

    CAS  PubMed  Google Scholar 

  54. La Fontaine, S. & Mercer, J.F. Trafficking of the copper-ATPase ATP7A and ATP7B: role in copper homeostasis. Arch. Biochem. Biophys. 463, 149–167 (2007).

    CAS  PubMed  Google Scholar 

  55. Huster, D. et al. Consequences of copper accumulation in the livers of the Atp7b−/− (Wilson disease gene) knockout mice. Am. J. Pathol. 168, 423–434 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Hamza, I., Prohaska, J. & Gitlin, J.D. Essential role for Atox1 in the copper-mediated intracellular trafficking of the Menkes ATPase. Proc. Natl. Acad. Sci. USA 100, 1215–1220 (2003).

    CAS  PubMed  Google Scholar 

  57. Hellman, N.E. et al. Mechanisms of copper incorporation into human ceruloplasmin. J. Biol. Chem. 277, 46632–46638 (2002).

    CAS  PubMed  Google Scholar 

  58. De Freitas, J.M., Liba, A., Meneghini, R., Valentine, J.S. & Gralla, E.B. Yeast lacking Cu-Zn superoxide dismutase show altered iron homeostasis. Role of oxidative stress in iron metabolism. J. Biol. Chem. 275, 11645–11649 (2000).

    CAS  PubMed  Google Scholar 

  59. Knight, S.A., Labbe, S., Kwon, L.F., Kosman, D.J. & Thiele, D.J. A widespread transposable element masks expression of a yeast copper transport gene. Genes Dev. 10, 1917–1929 (1996).

    CAS  PubMed  Google Scholar 

  60. Gralla, E.B. & Valentine, J.S. Null mutants of Saccharomyces cerevisiae Cu,Zn superoxide dismutase: characterization and spontaneous mutation rates. J. Bacteriol. 173, 5918–5920 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Elchuri, S. et al. CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24, 367–380 (2005).

    CAS  PubMed  Google Scholar 

  62. Furukawa, Y. & O'Halloran, T.V. Amyotrophic lateral sclerosis mutations have the greatest destabilizing effect on the apo- and reduced form of SOD1, leading to unfolding and oxidative aggregation. J. Biol. Chem. 280, 17266–17274 (2005).

    CAS  PubMed  Google Scholar 

  63. Furukawa, Y., Torres, A.S. & O'Halloran, T.V. Oxygen-induced maturation of SOD1: a key role for disulfide formation by the copper chaperone CCS. EMBO J. 23, 2872–2881 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Lamb, A.L., Torres, A.S., O'Halloran, T.V. & Rosenzweig, A.C. Heterodimeric structure of superoxide dismutase in complex with its metallochaperone. Nat. Struct. Biol. 8, 751–755 (2001).

    CAS  PubMed  Google Scholar 

  65. Field, L.S., Furukawa, Y., O'Halloran, T.V. & Culotta, V.C. Factors controlling the uptake of yeast copper/zinc superoxide dismutase into mitochondria. J. Biol. Chem. 278, 28052–28059 (2003).

    CAS  PubMed  Google Scholar 

  66. Okado-Matsumoto, A. & Fridovich, I. Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria. J. Biol. Chem. 276, 38388–38393 (2001).

    CAS  PubMed  Google Scholar 

  67. Sturtz, L.A., Diekert, K., Jensen, L.T., Lill, R. & Culotta, V.C. A fraction of yeast Cu,Zn-superoxide dismutase and its metallochaperone, CCS, localize to the intermembrane space of mitochondria. A physiological role for SOD1 in guarding against mitochondrial oxidative damage. J. Biol. Chem. 276, 38084–38089 (2001).

    CAS  PubMed  Google Scholar 

  68. Corson, L.B., Strain, J.J., Culotta, V.C. & Cleveland, D.W. Chaperone-facilitated copper binding is a property common to several classes of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants. Proc. Natl. Acad. Sci. USA 95, 6361–6366 (1998).

    CAS  PubMed  Google Scholar 

  69. Wong, P.C. et al. Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase. Proc. Natl. Acad. Sci. USA 97, 2886–2891 (2000).

    CAS  PubMed  Google Scholar 

  70. Jensen, L.T. & Culotta, V.C. Activation of CuZn superoxide dismutases from Caenorhabditis elegans does not require the copper chaperone CCS. J. Biol. Chem. 280, 41373–41379 (2005).

    CAS  PubMed  Google Scholar 

  71. Carroll, M.C. et al. Mechanisms for activating Cu- and Zn-containing superoxide dismutase in the absence of the CCS Cu chaperone. Proc. Natl. Acad. Sci. USA 101, 5964–5969 (2004).

    CAS  PubMed  Google Scholar 

  72. Carroll, M.C. et al. The effects of glutaredoxin and copper activation pathways on the disulfide and stability of Cu,Zn superoxide dismutase. J. Biol. Chem. 281, 28648–28656 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Jeney, V. et al. Role of antioxidant-1 in extracellular superoxide dismutase function and expression. Circ. Res. 96, 723–729 (2005).

    CAS  PubMed  Google Scholar 

  74. Qin, Z., Itoh, S., Jeney, V., Ushio-Fukai, M. & Fukai, T. Essential role for the Menkes ATPase in activation of extracellular superoxide dismutase: implication for vascular oxidative stress. FASEB J. 20, 334–336 (2006).

    CAS  PubMed  Google Scholar 

  75. Balamurugan, K. & Schaffner, W. Copper homeostasis in eukaryotes: teetering on a tightrope. Biochim. Biophys. Acta 1763, 737–746 (2006).

    CAS  PubMed  Google Scholar 

  76. Bird, A.J. Metallosensors, the ups and downs of gene regulation. Adv. Microb. Physiol. 53, 231–267 (2008).

    CAS  PubMed  Google Scholar 

  77. Bertinato, J. & L'Abbe, M.R. Copper modulates the degradation of copper chaperone for Cu,Zn superoxide dismutase by the 26 S proteosome. J. Biol. Chem. 278, 35071–35078 (2003).

    CAS  PubMed  Google Scholar 

  78. West, E.C. & Prohaska, J.R. Cu,Zn-superoxide dismutase is lower and copper chaperone CCS is higher in erythrocytes of copper-deficient rats and mice. Exp. Biol. Med. (Maywood) 229, 756–764 (2004).

    CAS  Google Scholar 

  79. Lamb, A.L. et al. Crystal structure of the copper chaperone for superoxide dismutase. Nat. Struct. Biol. 6, 724–729 (1999).

    CAS  PubMed  Google Scholar 

  80. Caruano-Yzermans, A.L., Bartnikas, T.B. & Gitlin, J.D. Mechanisms of the copper-dependent turnover of the copper chaperone for superoxide dismutase. J. Biol. Chem. 281, 13581–13587 (2006).

    CAS  PubMed  Google Scholar 

  81. Schmidt, P.J., Kunst, C. & Culotta, V.C. Copper activation of superoxide dismutase 1 (SOD1) in vivo. Role for protein-protein interactions with the copper chaperone for SOD1. J. Biol. Chem. 275, 33771–33776 (2000).

    CAS  PubMed  Google Scholar 

  82. Brown, N.M., Torres, A.S., Doan, P.E. & O'Halloran, T.V. Oxygen and the copper chaperone CCS regulate posttranslational activation of Cu,Zn superoxide dismutase. Proc. Natl. Acad. Sci. USA 101, 5518–5523 (2004).

    CAS  PubMed  Google Scholar 

  83. Lamb, A.L., Wernimont, A.K., Pufahl, R.A., O'Halloran, T.V. & Rosenzweig, A.C. Crystal structure of the second domain of the human copper chaperone for superoxide dismutase. Biochemistry 39, 1589–1595 (2000).

    CAS  PubMed  Google Scholar 

  84. Nittis, T. & Gitlin, J.D. Role of copper in the proteosome-mediated degradation of the multicopper oxidase hephaestin. J. Biol. Chem. 279, 25696–25702 (2004).

    CAS  PubMed  Google Scholar 

  85. Sazinsky, M.H. et al. Characterization and structure of a Zn2+ and [2Fe-2S]-containing copper chaperone from Archaeoglobus fulgidus. J. Biol. Chem. 282, 25950–25959 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Schaible, U.E. & Kaufmann, S.H. Iron and microbial infection. Nat. Rev. Microbiol. 2, 946–953 (2004).

    CAS  PubMed  Google Scholar 

  87. Prentice, A.M., Ghattas, H. & Cox, S.E. Host-pathogen interactions: can micronutrients tip the balance? J. Nutr. 137, 1334–1337 (2007).

    CAS  PubMed  Google Scholar 

  88. Doherty, C.P. Host-pathogen interactions: the role of iron. J. Nutr. 137, 1341–1344 (2007).

    CAS  PubMed  Google Scholar 

  89. Jung, W.H., Sham, A., White, R. & Kronstad, J.W. Iron regulation of the major virulence factors in the AIDS-associated pathogen Cryptococcus neoformans. PLoS Biol. 4, e410 (2006).

    PubMed  PubMed Central  Google Scholar 

  90. Lin, X. & Heitman, J. The biology of the Cryptococcus neoformans species complex. Annu. Rev. Microbiol. 60, 69–105 (2006).

    CAS  PubMed  Google Scholar 

  91. Fan, W., Kraus, P.R., Boily, M.J. & Heitman, J. Cryptococcus neoformans gene expression during murine macrophage infection. Eukaryot. Cell 4, 1420–1433 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Feldmesser, M., Kress, Y., Novikoff, P. & Casadevall, A. Cryptococcus neoformans is a facultative intracellular pathogen in murine pulmonary infection. Infect. Immun. 68, 4225–4237 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Waterman, S.R. et al. Role of a CUF1/CTR4 copper regulatory axis in the virulence of Cryptococcus neoformans. J. Clin. Invest. 117, 794–802 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Lin, X., Huang, J.C., Mitchell, T.G. & Heitman, J. Virulence attributes and hyphal growth of C. neoformans are quantitative traits and the MATalpha allele enhances filamentation. PLoS Genet. 2, e187 (2006).

    PubMed  PubMed Central  Google Scholar 

  95. Nielsen, K. et al. Cryptococcus neoformans {alpha} strains preferentially disseminate to the central nervous system during coinfection. Infect. Immun. 73, 4922–4933 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Noverr, M.C., Williamson, P.R., Fajardo, R.S. & Huffnagle, G.B. CNLAC1 is required for extrapulmonary dissemination of Cryptococcus neoformans but not pulmonary persistence. Infect. Immun. 72, 1693–1699 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Walton, F.J., Idnurm, A. & Heitman, J. Novel gene functions required for melanization of the human pathogen Cryptococcus neoformans. Mol. Microbiol. 57, 1381–1396 (2005).

    CAS  PubMed  Google Scholar 

  98. Huffnagle, G.B. et al. Down-regulation of the afferent phase of T cell-mediated pulmonary inflammation and immunity by a high melanin-producing strain of Cryptococcus neoformans. J. Immunol. 155, 3507–3516 (1995).

    CAS  PubMed  Google Scholar 

  99. Casadevall, A., Rosas, A.L. & Nosanchuk, J.D. Melanin and virulence in Cryptococcus neoformans. Curr. Opin. Microbiol. 3, 354–358 (2000).

    CAS  PubMed  Google Scholar 

  100. Heitman, J., Filler, S.G., Edwards, J.E.J. & Mitchell, A.P. Molecular Principles of Fungal Pathogenesis 3–666 (American Society for Microbiology, Washington, DC, 2006).

    Google Scholar 

  101. Hwang, C.S. et al. Copper- and zinc-containing superoxide dismutase (Cu/ZnSOD) is required for the protection of Candida albicans against oxidative stresses and the expression of its full virulence. Microbiology 148, 3705–3713 (2002).

    CAS  PubMed  Google Scholar 

  102. Cox, G.M. et al. Superoxide dismutase influences the virulence of Cryptococcus neoformans by affecting growth within macrophages. Infect. Immun. 71, 173–180 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Hooper, L.V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank members of the Thiele laboratory for helpful comments and suggestions; we also thank the many laboratories, both cited and not cited in this review due to space limitations, who have contributed to this field of investigation. B.-E.K. is supported by a Leon Golberg Memorial Postdoctoral Fellowship, and T.N. is supported by a Postdoctoral Fellowship from the Portuguese Foundation for Science and Technology (SFRH/BD/24352/2005). Work in our laboratory on copper homeostasis is supported by US National Institutes of Health grants GM41840 and DK074192 and by a grant from the International Copper Association, Ltd to D.J.T.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dennis J Thiele.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, BE., Nevitt, T. & Thiele, D. Mechanisms for copper acquisition, distribution and regulation. Nat Chem Biol 4, 176–185 (2008). https://doi.org/10.1038/nchembio.72

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.72

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing