Human Molecular Genetics Advance Access published online on June 30, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh197
© 2004 by Oxford University Press
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Montreal Neurological Institute, McGill University, Montreal, Canada H3A 2B4; Department of Human Genetics, McGill University, Montreal, Canada H3A 2B4
* To whom correspondence should be addressed. E-mail: eric{at}ericpc.mni.mcgill.ca.
Human SCO1 and SCO2 are paralogous genes that code for metallochaperone proteins with essential, but poorly understood, roles in copper delivery to cytochrome c oxidase (COX). Mutations in these genes produce tissue-specific COX deficiencies associated with distinct clinical phenotypes, although both are ubiquitously expressed. To investigate the molecular function of the SCO proteins we characterized the mitochondrial copper delivery pathway in SCO1 and SCO2 patient backgrounds. Immunoblot analysis of patient cell lines showed reduced levels of the mutant proteins, resulting in a defect in COX assembly, and the appearance of a common assembly intermediate. Overexpression of the metallochaperone COX17 rescued the COX deficiency in SCO2 but not SCO1 patient cells. Overexpression of either wild-type SCO protein in the reciprocal patient background resulted in a dominant-negative phenotype, suggesting a physical interaction between SCO1 and SCO2. Chimeric proteins, constructed from the C-terminal copper-binding and N-terminal matrix domains of the two SCO proteins failed to complement the COX deficiency in either patient background, but mapped the dominant-negative phenotype in the SCO2 background to the N-terminal domain of SCO1, the most divergent part of the two SCO proteins. Our results demonstrate that the human SCO proteins have non-overlapping, cooperative functions in mitochondrial copper delivery. Size exclusion chromatography suggests that both proteins function as homodimers. We propose a model in which COX17 delivers copper to SCO2, which in turn transfers it directly to the CuA site at an early stage of COX assembly in a reaction that is facilitated by SCO1.
Article
Human SCO1 and SCO2 have independent, cooperative functions in copper delivery to cytochrome c oxidase
2 Montreal Neurological Institute, McGill University, Montreal, Canada H3A 2B4
3 Department of Pathology and Laboratory Medicine, Children's & Women's Health Centre of British Columbia, Vancouver, Canada V6H 3N1
4 Metabolic Disease Centre Munich-Schwabing and Institute of Clinical Chemistry, Molecular Diagnostics and Mitochondrial Genetics, 80804 Munich, Germany
5 Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, Canada, H3A 2B4; Department of Human Genetics, McGill University, Montreal, Canada H3A 2B4
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. C. Leary, F. Sasarman, T. Nishimura, and E. A. Shoubridge Human SCO2 is required for the synthesis of CO II and as a thiol-disulphide oxidoreductase for SCO1 Hum. Mol. Genet., June 15, 2009; 18(12): 2230 - 2240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. White, T. Kambe, Y. G. Fulcher, S. W. Sachdev, A. I. Bush, K. Fritsche, J. Lee, T. P. Quinn, and M. J. Petris Copper transport into the secretory pathway is regulated by oxygen in macrophages J. Cell Sci., May 1, 2009; 122(9): 1315 - 1321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Stiburek, K. Vesela, H. Hansikova, H. Hulkova, and J. Zeman Loss of function of Sco1 and its interaction with cytochrome c oxidase Am J Physiol Cell Physiol, May 1, 2009; 296(5): C1218 - C1226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Turski and D. J. Thiele New Roles for Copper Metabolism in Cell Proliferation, Signaling, and Disease J. Biol. Chem., January 9, 2009; 284(2): 717 - 721. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gonzalez, A. Reyes-Jara, M. Suazo, W. J Jo, and C. Vulpe Expression of copper-related genes in response to copper load Am. J. Clinical Nutrition, September 1, 2008; 88(3): 830S - 834S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Rigby, P. A. Cobine, O. Khalimonchuk, and D. R. Winge Mapping the Functional Interaction of Sco1 and Cox2 in Cytochrome Oxidase Biogenesis J. Biol. Chem., May 30, 2008; 283(22): 15015 - 15022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Banci, I. Bertini, S. Ciofi-Baffoni, T. Hadjiloi, M. Martinelli, and P. Palumaa Mitochondrial copper(I) transfer from Cox17 to Sco1 is coupled to electron transfer PNAS, May 13, 2008; 105(19): 6803 - 6808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Son, S. C. Leary, N. Romain, F. Pierrel, D. R. Winge, R. G. Haller, and J. L. Elliott Isolated Cytochrome c Oxidase Deficiency in G93A SOD1 Mice Overexpressing CCS Protein J. Biol. Chem., May 2, 2008; 283(18): 12267 - 12275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Fontanesi, C. Jin, A. Tzagoloff, and A. Barrientos Transcriptional activators HAP/NF-Y rescue a cytochrome c oxidase defect in yeast and human cells Hum. Mol. Genet., March 15, 2008; 17(6): 775 - 788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. N. Yurgel, J. Berrocal, C. Wilson, and M. L. Kahn Pleiotropic effects of mutations that alter the Sinorhizobium meliloti cytochrome c respiratory system Microbiology, February 1, 2007; 153(2): 399 - 410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Banci, I. Bertini, V. Calderone, S. Ciofi-Baffoni, S. Mangani, M. Martinelli, P. Palumaa, and S. Wang A hint for the function of human Sco1 from different structures PNAS, June 6, 2006; 103(23): 8595 - 8600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Cobine, F. Pierrel, S. C. Leary, F. Sasarman, Y.-C. Horng, E. A. Shoubridge, and D. R. Winge The P174L Mutation in Human Sco1 Severely Compromises Cox17-dependent Metallation but Does Not Impair Copper Binding J. Biol. Chem., May 5, 2006; 281(18): 12270 - 12276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Schoenfeld, E. Napoli, A. Wong, S. Zhan, L. Reutenauer, D. Morin, A. R. Buckpitt, F. Taroni, B. Lonnerdal, M. Ristow, et al. Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells Hum. Mol. Genet., December 15, 2005; 14(24): 3787 - 3799. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-C. Horng, S. C. Leary, P. A. Cobine, F. B. J. Young, G. N. George, E. A. Shoubridge, and D. R. Winge Human Sco1 and Sco2 Function as Copper-binding Proteins J. Biol. Chem., October 7, 2005; 280(40): 34113 - 34122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. Carr, A. B. Maxfield, Y.-C. Horng, and D. R. Winge Functional Analysis of the Domains in Cox11 J. Biol. Chem., June 17, 2005; 280(24): 22664 - 22669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Williams, C. Sue, G. S. Banting, H. Yang, D. M. Glerum, W. A. Hendrickson, and E. A. Schon Crystal Structure of Human SCO1: IMPLICATIONS FOR REDOX SIGNALING BY A MITOCHONDRIAL CYTOCHROME c OXIDASE "ASSEMBLY" PROTEIN J. Biol. Chem., April 15, 2005; 280(15): 15202 - 15211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Cardol, D. Gonzalez-Halphen, A. Reyes-Prieto, D. Baurain, R. F. Matagne, and C. Remacle The Mitochondrial Oxidative Phosphorylation Proteome of Chlamydomonas reinhardtii Deduced from the Genome Sequencing Project Plant Physiology, February 1, 2005; 137(2): 447 - 459. [Full Text] [PDF]
|
|