Intl. Copper Meeting
2011

SWISS COPPER GROUP

Department Clinical Research
University of Berne
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Team Members

Marc Solioz	Thomas Weber	Stefano Mancini
Salima Mathews	Helge Abicht

Research Areas

Copper Homeostasis in Bacteria

Copper-Responsive Repressors

The CopR Regulon of Lactococcus lactis

Surface Killing of Bacteria

Diagnosis of Wilson Disease

Documentation/Courses

Buffer & Media Book (restricted site)	Bionews Mailing List	Bioinformatics Resource	Know-how Manager
Orders (restricted site)	Good Lab1 Practices (restricted site)	Working with Radioactivity (restricted site)	Publications
Lab Manual (restricted site)	Stock of Bacteria (restricted site)	Job Safety and Health (restricted site)	Genomes in progress (restricted site)

The Model Organisms - Enterococcus hirae and Lactococcus lactis IL1403

We are studying copper homeostasis in the model organisms Enterococcus hirae and Lactococcus lactis. These Gram-positive lactic acid bacteria have only a single cell membrane and generally grow fermentatively. However, when supplied with hemin, they express cytochrome oxidase and can respire. The genome of L. lactis has been completely sequenced, making it particularly suitable for proteomics analysis. View the L. lactis genome page.i

Scanning electron micrograph of E. hirae.
View a Gram-staining of a sputum.

Scanning electron microscopy of Enterococcus hirae

E. hirae Copper Homeostasis - Overview

In Enterococcus hirae, copper homeostasis is effected by the copoperon. It encodes two P-type ATPases, CopA and CopB, that have homology to the human Menkes and Wilson copper ATPases. They serve in the uptake and secretion of copper, respectively. Take a look at the ATPase database.

CopY is a copper responsive repressor that regulates the expression of all four cop genes, and CopZ a copper chaperone that routes copper intracellularly. Lactococcus lactis has a similar cop operon, but it does not encompass a copB gene. Instead, the copB gene is located on a separate, monocistronic operon. We study the structure and function of these copper homeostatic genes and try to discover new ones.
Copper homeostasis in E. hirae. Copper enters cells via CopA or unknown channels. Excess copper is picked up by the CopZ chaperone and delivered to CopB for secretion the to the CopY repressor for induction of the cop operon. Excess CopZ is proteolyzed.

Function of the cop-operon genes

CopY-type Copper-Responsive Repressors

CopY-type repressors are ubiquitous in firmicutes. They regulated the induction of copper homeostatic genes by copper. These repressors represent a new family of 'winged helix' proteins involved in metallo-regulation of genes. We have solved the structure of the CopY-type repressor of L. lactis, which is called CopR.

The figure on the right shows the structure of the DNA binding domain of CopR (blue) overlayed on the structure of BlaI (gold), a very similar winged helix protein involved in the regulation of antibiotic resistance in Bacillus licheniformis. The proteins have the general fold α1-β1-α2-α3-β2-β3.

The CopR Regulon of Lactococcus lactis

In Lactococcus lactis, 14 genes are under the control of the copper-responsive repressor CopR. We call this the CopR regulon. Some of these genes have an obvious role in copper homeostasis. For example the copR gene encodes the CopR regulator which regulates the CopR regulon, copZ encodes the copper chaperone, and copA encodes the copper-exporting CopA ATPase. The role of most of the other genes of the CopR regulon is unclear and work on their funtion is currently in progress.

The picture to the right shows the genes and operons of L. lactis which are under the control of the CopR repressor and thus copper regulated.

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**Surface Killing of Bacteria**
Copper and copper alloys have bactericidal activity against a variety of Gram-positive and Gram negative bacteria. The mechanism of killing is however unclear. Current studies in our lab aim at understanding how copper kills bacteria and to test for the emergence of resistance. Using biosensors which monitor cytoplasmic copper levels, it will be tested if a rise in cytoplasmic copper participates in killing. It will also be analyzed if toxic chemicals are generated at the copper surface when it is in contact with bacterial components, such as cell wall compounds or membrane lipids. Finally, it will be assessed if resistant bacterial strains can be generated by mutagenesis. The findings should help to clarify the mechanism of the bactericidal activity of copper surfaces and to better judge the possibility of the mergence of resistant strain.

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Education

**Technical Expertise**
Cloning, Screening, RACE, DNA sequencing Purification of membrane proteins Transport measurements Electroporation Purification and reconstitution of membrane proteins Southern, Northern und Western blotting Real-time quantitative PCR 2D gel electrophoresis 2D liquid separation (ProteomeLab PF 2D) Dynamic light scattering

**Educational Opportunities**
Diploma work in biochemistry/molecular biology PhD thesis in biochemistry/molecular biology Doctorates for MDs Bioinformatics Molecular biology Membrane biochemistry

Publications Relevant to Copper

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Abicht, H. K., Martinez, J., Layer, G., Jahn, D., and Solioz, M. (2012) Lactococcus lactis HemW (HemN) is a heme-binding protein with a putative role in heme trafficking. Biochem. J., in press. PDF (534 kb).
Mermod, M., Magnani, D., Solioz, M., and Stoyanov, J. V. (2012) The copper-inducible ComR (YcfQ) repressor regulates expression of ComC (YcfR), which affects copper permeability of the outer membrane of Escherichia coli. BioMetals 25, 33-43. PDF (216 kb).
Mancini, S., Abicht, H. K., Karnachuk, O. V., and Solioz, M. (2011) Genome sequence of Desulfovibrio sp. A2, a highly copper resistant, sulfate-reducing bacterium isolated from effluents of a zinc smelter at the Urals. J. Bacteriol. 193, 6793-6794. PDF (36 kb).
Abicht, H. K., Mancini, S., Karnachuk, O. V., and Solioz, M. (2011) Genome sequence of Desulfosporosinus sp. OT, an acidophilic sulfate-reducing bacterium from copper mining waste in Norilsk, Northern Siberia. J. Bacteriol. 193, 6104-6105. PDF (38 kb).
Solioz, M., Mancini, S., Abicht, H. K., and Mermod, M. (2011) The lactic acid bacteria response to metal stress. In "Stress response of lactic acid bacteria" (Tsakalidou, E. and Papadimitriou, K., eds.) Springer, Heidelberg, pp. 163-195. PDF (570 kb).
Solioz, M. (2011) Copper kills bacteria - The end of hospital-acquired infections? Scienzainrete.
Solioz, M. (2011) Il rame... chi l'avrebbe detto? Scienzainrete.
Solioz, M. (2011) Wirkung und Gebrauch von antimikrobiellem Kupfer. In Angewandte medizinische Technik. Würzburg, 2011, pp. 121-123. PDF (946 kb).
Grass, G., Rensing, C., and Solioz, M. (2011) Metallic copper as an antimicrobial surface. Appl. Environ. Microbiol. 77, 1541-1547. PDF (291 kb).
Martinez, J., Mancini, S., Tauberger, E., Weise, C., Saenger, W., and Solioz, M. (2011) Regulation and structure of YahD, a copper inducible α/β serine hydrolase of Lactococcus lactis IL1403. FEMS Microbiol. Lett. 314, 57-66. PDF (1063 kb).
Aigner, E., Strasser, M., Haufe, H., Sonnweber, T., Hohla, F., Stadlmayr, A., Solioz, M., Tilg, H., Patsch, W., Weiss, G., Stickel, F., and Datz, C. (2010) A role for low hepatic copper concentrations in non-alcoholic fatty liver disease. Am. J. Gastroenterol. 105, 1978-1985. PDF (259 kb).
Danzeisen, R., Stern, B. R., Aggett, P. J., Deveau, M., Plunkett, L., Chambers, A., Krewski, D., Levy, L. S., McArdle, H. J., Keen, C. L., Araya, M. and Solioz, M. (2010) Letter to the editor and reply: Toxicity of copper in drinking water. J. Toxicol. Environ. Health B Crit. Rev. 13, 449-459. PDF (83 kb).
Mermod, M., Mourlane, F., Waltersperger, S., Oberholzer, A. E., Baumann, U., and Solioz, M. (2010) Structure and function of CinD (YtjD) of Lactococcus lactis, a copper-induced nitroreductase involved in defence against oxidative stress. J. Bacteriol. 192, 4172-4180. PDF (1093 kb).
Solioz, M., Abicht, H. K., and Mourlane, F. (2010) Kupfer - Einem Spurenelement auf der Spur. Schweiz. Med. Forum 10, 379-383. PDF (916 kb).
Molteni, C., Abicht, H. K., and Solioz, M. (2010) Killing of bacteria by copper surfaces involves dissolved copper. Appl. Environ. Microbiol. 76, 4099-4101. PDF (147 kb).
Stoyanov, J. V., Mancini, S., Lu, Z. H., Mourlane, F., Poulsen, K. R., Wimmer, R., and Solioz, M. (2010) The stress response regulator Gls24 is induced by copper and interacts with the CopZ copper chaperone of Enterococcus hirae. FEMS Microbiol. Lett. 302, 69-75. PDF (488 kb).
Solioz, M., Abicht, H. K., Mermod, M., and Mancini, S. (2010) Response of Gram-positive bacteria to copper stress. J. Biol. Inorg. Chem. 15, 3-14. PDF (946 kb).
Lübben, M., Portmann, R., Kock, G., Stoll, R., Young, M. M., and Solioz M. (2009) Structural model of the CopA copper ATPase of Enterococcus hirae based on chemical cross-linking. BioMetals 22, 363-375. PDF (520 kb).
Cantini, F., Banci, L., Magnani, D., and Solioz M. (2009) The copper-responsive repressor CopR of Lactococcus lactis is a 'winged helix' protein. Biochem. J. 419, 493-499. PDF (545 kb).
Danzeisen, R., Araya, M., Harrison, B., Keen, C., Solioz, M., Thiele, D., and McArdle, H. J. (2008) How reliable and robust are current biomarkers for copper status? - reply by Danzeisen et al. Br. J. Nutr. 100, 1343-1344. PDF (46 kb).
Magnani, D., Barré, O., Gerber, S. D., and Solioz, M. (2008) Characterization of the CopR regulon of Lactococcus lactis IL1403. J. Bacteriol. 190, 535-546. PDF (805 kb).
Danzeisen, R., Araya, M., Harrison, B., Keen, C., Solioz, M., Thiele, D., and McArdle, H. J. (2007) How reliable and robust are current biomarkers for copper status? Br. J. Nutr. 98, 676-683. PDF (1106 kb).
Barré, O., Mourlane, F., and Solioz, M. (2007) Copper-induction of lactate oxidase (LctO) of Lactococcus lactis: A novel metal stress-response. J. Bacteriol. 189, 5947-5954. PDF (263 kb).
Gerber, S. D., and Solioz, M. (2007) Efficient transformation of Lactococcus lactis IL1403 and generation of knock-out mutants by homologous recombination. J. Basic Microbiol. 47, 281-286. PDF (181 kb).
Magnani, D., and Solioz, M. (2007) How bacteria handle copper. In Bacterial Transition Metal Homeostasis (Nies, D. H., and Silver, S., eds.) Springer, Heidelberg, pp. 259-285. PDF (569 kb).
Stern, B., Solioz, M., Krewski, D., Aggett, P. J., Aw, T.-C., Baker, S., Crump, K., Doursen, M., Haber, L., Hertzberg, R., Keen, C. L., Meek, B., Rudenko, L., Schoeny, R., Slob, W., and Starr, T. (2007) J. Toxicol. Environ. Health 10, 157-222. PDF (457 kb).
Barré, O., and Solioz, M. (2006) Improved protocol for chromatofocusing on the ProteomeLab PF2D. Proteomics 60, 5096-5098. PDF (208 kb).
Portmann, R., Poulsen, K. R., Wimmer, R., and Solioz, M. (2006) CopY-like copper inducible repressors are putative 'winged helix' proteins. BioMetals 19, 61-70. PDF (495 kb).
Magnani, D., and Solioz, M. (2005) Copper chaperone cycling and degradation in the regulation of the cop operon of Enterococcus hirae. BioMetals 18, 407-412. PDF (313 kb).
Portmann, R., and Solioz, M. (2005) Purification and functional reconstitution of the human Wilson copper ATPase, ATP7B. FEBS Lett. 579, 3589-3595. PDF (177 kb), supplementary information (61 kb).
Knöpfel, M, and Solioz, M. (2005) ATP-driven copper transport across the intestinal brush border membrane. BBRC 330, 645-652. PDF (230 kb).
Bissig, K.-D., Honer, M., Zimmermann, K., Summer, K. H., and Solioz, M. (2005) Whole animal copper flux assessed by positron emission tomography in the Long-Evans cinnamon rat − a feasibility study. BioMetals 18, 83-88. PDF (220 kb), supplementary on-line material.
Portmann, R., Magnani, D., Stoyanov, J. V., Schmechel, A., Multhaup, G., and Solioz, M. (2004). Interaction kinetics of the copper-responsive CopY repressor with the cop promoter of Enterococcus hirae. J. Biol. Inorg. Chem. 9, 396-402. PDF (1619 kb).
Stoyanov, J. V., Magnani, D., and Solioz, M. (2003) Measurement of cytosolic copper, silver, and gold with a lux biosensor shows copper and silver, but not gold, efflux by the CopA ATPase of Escherichia coli. FEBS Lett. 546, 391-394. PDF (199 kb).
Solioz, M., and Stoyanov, J. V. (2003) Copper homeostasis in Enterococcus hirae. FEMS Microbiol. Rev. 27, 183-195. PubMed. PDF (416 kb).
Baerlocher, K., and Solioz, M. (2003) Disorders of copper, zinc and iron metabolism. In: A Physician's Guide to the Laboratory - Diagnosis of Metabolic Diseases, N. Blau, M. Duran, M. E. Blaskovics, and K. M. Gibson, eds., (Heidelberg, Springer), pp. 631-658. PDF (4825 kb).
Lu, Z. H., Dameron, C. T., and Solioz, M. (2003) The Enterococcus hirae paradigm of copper homeostasis: Copper chaperone turnover, interactions, and transactions. BioMetals 16, 137-143. PDF (183 kb).
Lu, Z. H., and Solioz, M. (2002) Bacterial copper transport. In Copper Containing Proteins, J. S. Valentine, E. B. Gralla, eds. Series title: Advances in Protein Chemistry, vol. 60 (San Diego, CA: Academic Press), pp. 93-121. PDF (5989 kp).
Solioz, M. (2002). Role of proteolysis in copper homoeostasis. Biochem. Soc. Trans. 30, 688-691. PDF (81 kb).
Cobine, P., Jones, C. E., Wickramasinghe, W. A., Solioz, M., and Dameron, C. T. (2002). Interaction of copper binding proteins from Enterococcus hirae. In Handbook of Copper Pharmacology and Toxicology, E. J. Massaro, ed. (Totowa, NJ: Humana Press), pp. 177-186. PDF (6119 kb).
Wimmer, R., Dameron, C. T., and Solioz, M. (2002). Molecular hardware of copper homeostasis in Enterococcus hirae. In Handbook of Copper Pharmacology and Toxicology, E. J. Massaro, ed. (Totowa, NJ: Humana Press), pp. 527-542. PDF (3282 kb).
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Cobine, P. A., George, G. N., Jones, C. E., Wickramasinghe, W. A., Solioz, M., and Dameron, C. T. (2002). Copper Transfer from the Cu(I) Chaperone, CopZ, to the Repressor, Zn(II)CopY: Metal Coordination Environments and Protein Interactions. Biochemistry 41, 5822-5829. PDF (139 kb). Editor's Choice, Science 296, 619 (2002).
Knöpfel, M, and Solioz, M. (2002) Characterization of a cytochrome b₅₅₈ ferric/cupric reductase from rabbit duodenal brush border membranes. Biochem. Biophys. Res. Commun. 291, 220-225. PDF (93 kb).
Lu, Z. H., and Solioz, M. (2001) Copper induced proteolysis of the CopZ copper chaperone of Enterococcus hirae. J. Biol. Chem. 276, 47822-47827. PDF (174 kb).
Bissig, K.-D., Voegelin, T. C., and Solioz, M. (2001) Tetrathiomolybdate inhibition of the Enterococcus hirae CopB copper ATPase. FEBS Lett. 507, 367-370. PDF (92 kb).
Multhaup, G., Strausak, D., Bissig, K.-D., and Solioz, M. (2001) Interaction of the CopZ copper chaperone with the CopA copper ATPase of Enterococcus hirae assessed by surface plasmon resonance. Biochem. Biophys. Res. Commun. 288, 172-177. PDF (84 kb).
Solioz, M. (2001). Bacterial copper transport. In Microbial Transport Systems (Winkelmann, G., ed.) Wiley, Weinheim, pp. 361-376. PDF (320 kb).
Bissig, K.-D., Wunderli-Ye, H., Duda, P., and Solioz, M. (2001) Structure-function analysis of purified Enterococcus hirae CopB copper ATPase: Effect of Menkes/Wilson disease mutation homologues. Biochem. J. 357, 217-223. PDF (227 kb).
Bissig, K.-D., La Fontaine, S., Mercer, J. F. B., and Solioz, M. (2001) Expression of the human Menkes ATPase in Xenopus laevis oocytes. Biol. Chem. 382, 711-714. PDF (195 kb).
Wunderli-Ye, H., and Solioz, M. (2001) Purification and functional analysis of the CopA copper ATPase of Enterococcus hirae. Biochem. Biophys. Res. Commun. 280, 713-719. PDF (138 kb).
Bissig, K.-D., Wunderli-Ye, H., and Solioz, M. (2000). Copper homeostasis in Enterococcus hirae: pumps, repressor, chaperone. In Metal Ions in Biology and Medicine. John Libbey Eurotext, Paris, pp. 133-136. PDF (878 kb).
Harrison, M. D., Jones, C. E., Solioz, M., and Dameron, C. T. (2000) Intracellular copper routing: The role of copper chaperones. Trends Biochem. Sci. 25, 29-32. PDF (592 kb).
Bissig, K.-D., Lu, Z.H., La Fontaine, S., Lockhart, P.J., Mercer, J.F.B., and Solioz, M. (1999) Unravelling copper homeostasis through the study of eukaryotic and prokaryotic model systems. In New Aspects of Trace Element Research (Abdulla, M., Chazot, G., and Bost, M., eds.) Smith-Gordon, East Preston, pp. 1-6. PDF (1225 kb).
Cobine, P., Wickramasinghe, W.A., Harrison, M.D., Weber, T., Solioz, M., and Dameron, C.T. (1999) The Enterococcus hirae copper chaperone CopZ delivers copper(I) to the CopY repressor. FEBS Lett. 445, 27-30. PDF (144 kb).
Lu, Z.H., Cobine, P., Dameron, C.T., and Solioz, M. (1999) How cells handle copper: A view from microbes. J. Trace Elem. Exp. Med. 12, 347-360. PDF (2923 kb).
Wimmer, R., Herrmann, T., Solioz, M., and Wüthrich, K. (1999) NMR structure and metal interactions of the CopZ copper chaperone. J. Biol. Chem. 274, 22597-22603. PDF (579 kb).
Wunderli-Ye, H., and Solioz, M. (1999) Effects of promoter mutations on the in vivo regulation of the cop operon of Enterococcus hirae by Copper(I) and Copper(II). Bichem. Biophys. Res. Commun. 259, 443-449. PDF (125 kb).
Wunderli-Ye, H., and Solioz, M. (1999) Copper homeostasis in Enterococcus hirae. In "Copper Transport and its Disorders: Molecular and Cellular Aspects" (Leone, A. and Mercer, J.F.B., eds.), Plenum, New York, pp. 261-270. PDF (2276 kb).
Solioz, M., and Bissig, K.-D. (1998) Wie (kein) Kupfer krank macht. Schweiz. Med. Wochenschr. 128, 1175-1180. PDF (1926 kb).
Wunderli-Ye, H., and Solioz, M. (1998) Regulation of the cop operon of Enterococcus hirae by the CopY repressor and copper. In "Metal Ions in Biology and Medicine" (Collery, P., Brätter, P., Negretti de Brätter, V., Khassanova, L. and Etienne, J.-C., eds.), John Libbey Eurotext, Paris, pp. 109-113. PDF (1537 kb).
Solioz, M. (1998) Copper homeostasis by CPX-type ATPases, the subclass of heavy metal P-type ATPases. In "Advances in molecular and cell biology" (Bittar, E. E. and Andersen, J. P., eds.) pp. 167-203. JAI Press Inc., London. PDF (8882 kb).
Solioz, M., and Camakaris, J. (1997) Acylphosphate formation by the Menkes copper ATPase. FEBS Lett. 412, 165-168. PDF (1615 kb).
Strausak, D., and Solioz, M. (1997) CopY is a copper-inducible repressor of the Enterococcus hirae copper ATPase. J. Biol. Chem. 272, 8932-8936. PDF (377 kb).
Wyler-Duda, and Solioz, M. (1996) Phosphoenzyme formation by purified, reconstituted copper ATPase of Enterococcus hirae. FEBS Lett. 399, 143-146. PDF (640 kb).
Solioz, M., and Vulpe, C. (1996) CPX-type ATPases: a class of P-type ATPases that pump heavy metals. TIBS 21, 237-241. PDF (869 kb).
Odermatt, A., and Solioz, M. (1995) Two trans-acting metalloregulatory proteins controlling expression of the copper-ATPases of Enterococcus hirae. J. Biol. Chem. 270, 4349-4354. PDF (310 kb).
Solioz, M., and Odermatt, A. (1995) Copper and silver transport by CopB-ATPase in membrane vesicles of Enterococcus hirae. J. Biol. Chem. 270, 9217-9221. PDF (140 kb).
Odermatt, A., Krapf, R. and Solioz, M. (1994) Induction of the putative copper ATPases, CopA and CopB, of Enterococcus hirae by Ag⁺ and Cu²⁺, and Ag⁺ extrusion by CopB. Biochem. Biophys. Res. Commun. 202, 44-48. PDF (230 kb).
Solioz, M., Odermatt, A., and Krapf, R. (1994) Copper pumping ATPases: common concepts in bacteria and man. FEBS Lett. 346, 44-47. PDF (310 kb).
Odermatt, A., Suter, H., Krapf, R., and Solioz, M. (1993) Primary structure of two P-type ATPases involved in copper homeostasis in Enterococcus hirae. J. Biol. Chem. 268 , 12775-12779. PDF (310 kb).
Odermatt, A., Suter, H., Krapf, R., and Solioz, M. (1992) An ATPase operon involved in copper resistance by Enterococcus hirae. Ann. N. Y. Acad. Sci. 671, 484-486. PDF (230 kb).
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Last updated: December 9, 2011