Human Molecular Genetics, 2001, Vol. 10, No. 4 361-370
© 2001 Oxford University Press
Effect of the toxic milk mutation (tx) on the function and intracellular localization of Wnd, the murine homologue of the Wilson copper ATPase
1Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, Australia and Centre for Cellular and Molecular Biology, School of Biological and Chemical Sciences, Deakin University, Burwood, VIC 3125, Australia, 2Centre for Microscopy and Microanalysis, 3Department of Physiology and Pharmacology and Centre for Molecular and Cellular Biology, University of Queensland, St Lucia, QLD 4072, Australia
Wilson disease is an autosomal recessive copper transport disorder resulting from defective biliary excretion of copper and subsequent hepatic copper accumulation and liver failure if not treated. The disease is caused by mutations in the ATP7B (WND) gene, which is expressed predominantly in the liver and encodes a copper-transporting P-type ATPase that is structurally and functionally similar to the Menkes protein (MNK), which is defective in the X-linked copper transport disorder Menkes disease. The toxic milk (tx) mouse has a clinical phenotype similar to Wilson disease patients and, recently, the tx mutation within the murine WND homologue (Wnd) of this mouse was identified, establishing it as an animal model for Wilson disease. In this study, cDNA constructs encoding the wild-type (Wnd-wt) and mutant (Wnd-tx) Wilson proteins (Wnd) were generated and expressed in Chinese hamster ovary (CHO) cells. The tx mutation disrupted the copper-induced relocalization of Wnd in CHO cells and abrogated Wnd-mediated copper resistance of transfected CHO cells. In addition, co-localization experiments demonstrated that while Wnd and MNK are located in the trans-Golgi network in basal copper conditions, with elevated copper, these proteins are sorted to different destinations within the same cell. Ultrastructural studies showed that with elevated copper levels, Wnd accumulated in large multi-vesicular structures resembling late endosomes that may represent a novel compartment for copper transport. The data presented provide further support for a relationship between copper transport activity and the copper-induced relocalization response of mammalian copper ATPases, and an explanation at a molecular level for the observed phenotype of tx mice.
+ These authors contributed equally to this work
§ To whom correspondence should be addressed at: Centre for Cellular and Molecular Biology, School of Biological and Chemical Sciences, Deakin University, Melbourne Campus, Building L, 221 Burwood Highway, Burwood, VIC 3125, Australia. Tel: +61 3 9251 7329; Fax: +61 3 9251 7328; Email: jmercer@deakin.edu.au
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. H. Weiss, J. Carbajo Lozoya, S. Tuma, D. Gotthardt, J. Reichert, R. Ehehalt, W. Stremmel, and J. Fullekrug Copper-Induced Translocation of the Wilson Disease Protein ATP7B Independent of Murr1/COMMD1 and Rab7 Am. J. Pathol., December 1, 2008; 173(6): 1783 - 1794. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Michalczyk, E. Bastow, M. Greenough, J. Camakaris, D. Freestone, P. Taylor, M. Linder, J. Mercer, and M. L. Ackland ATP7B Expression in Human Breast Epithelial Cells Is Mediated by Lactational Hormones J. Histochem. Cytochem., April 1, 2008; 56(4): 389 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P de Bie, P Muller, C Wijmenga, and L W J Klomp Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes J. Med. Genet., November 1, 2007; 44(11): 673 - 688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Lutsenko, N. L. Barnes, M. Y. Bartee, and O. Y. Dmitriev Function and Regulation of Human Copper-Transporting ATPases Physiol Rev, July 1, 2007; 87(3): 1011 - 1046. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Nyasae, R. Bustos, L. Braiterman, B. Eipper, and A. Hubbard Dynamics of endogenous ATP7A (Menkes protein) in intestinal epithelial cells: copper-dependent redistribution between two intracellular sites Am J Physiol Gastrointest Liver Physiol, April 1, 2007; 292(4): G1181 - G1194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-C. Wu, A. Gardarin, A. Martel, E. Mintz, F. Guillain, and P. Catty The Cadmium Transport Sites of CadA, the Cd2+-ATPase from Listeria monocytogenes J. Biol. Chem., October 6, 2006; 281(40): 29533 - 29541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Kelleher and B. Lonnerdal Mammary gland copper transport is stimulated by prolactin through alterations in Ctr1 and Atp7A localization Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R1181 - R1191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Lim, M. A. Cater, J. F. B. Mercer, and S. La Fontaine Copper-dependent Interaction of Dynactin Subunit p62 with the N Terminus of ATP7B but Not ATP7A J. Biol. Chem., May 19, 2006; 281(20): 14006 - 14014. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Guo, L. Nyasae, L. T. Braiterman, and A. L. Hubbard NH2-terminal signals in ATP7B Cu-ATPase mediate its Cu-dependent anterograde traffic in polarized hepatic cells Am J Physiol Gastrointest Liver Physiol, November 1, 2005; 289(5): G904 - G916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Harada, T. Kawaguchi, H. Kumemura, K. Terada, H. Ninomiya, E. Taniguchi, S. Hanada, S. Baba, M. Maeyama, H. Koga, et al. The Wilson Disease Protein ATP7B Resides in the Late Endosomes with Rab7 and the Niemann-Pick C1 Protein Am. J. Pathol., February 1, 2005; 166(2): 499 - 510. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Kelleher and B. Lonnerdal Low Vitamin A Intake Affects Milk Iron Level and Iron Transporters in Rat Mammary Gland and Liver J. Nutr., January 1, 2005; 135(1): 27 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lowe, A. Vieyra, P. Catty, F. Guillain, E. Mintz, and M. Cuillel A Mutational Study in the Transmembrane Domain of Ccc2p, the Yeast Cu(I)-ATPase, Shows Different Roles for Each Cys-Pro-Cys Cysteine J. Biol. Chem., June 18, 2004; 279(25): 25986 - 25994. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Phinney, B. Drisaldi, S. D. Schmidt, S. Lugowski, V. Coronado, Y. Liang, P. Horne, J. Yang, J. Sekoulidis, J. Coomaraswamy, et al. In vivo reduction of amyloid-{beta} by a mutant copper transporter PNAS, November 25, 2003; 100(24): 14193 - 14198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Kelleher and B. Lonnerdal Marginal Maternal Zn Intake in Rats Alters Mammary Gland Cu Transporter Levels and Milk Cu Concentration and Affects Neonatal Cu Metabolism J. Nutr., July 1, 2003; 133(7): 2141 - 2148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. B. Mercer and R. M. Llanos Molecular and Cellular Aspects of Copper Transport in Developing Mammals J. Nutr., May 1, 2003; 133(5): 1481S - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Petris, I. Voskoboinik, M. Cater, K. Smith, B.-E. Kim, R. M. Llanos, D. Strausak, J. Camakaris, and J. F. B. Mercer Copper-regulated Trafficking of the Menkes Disease Copper ATPase Is Associated with Formation of a Phosphorylated Catalytic Intermediate J. Biol. Chem., November 22, 2002; 277(48): 46736 - 46742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cobbold, S. Ponnambalam, M. J. Francis, and A. P. Monaco Novel membrane traffic steps regulate the exocytosis of the Menkes disease ATPase Hum. Mol. Genet., November 1, 2002; 11(23): 2855 - 2866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Tsivkovskii, J. F. Eisses, J. H. Kaplan, and S. Lutsenko Functional Properties of the Copper-transporting ATPase ATP7B (The Wilson's Disease Protein) Expressed in Insect Cells J. Biol. Chem., January 4, 2002; 277(2): 976 - 983. [Abstract] [Full Text] [PDF]
|
|