title: Atox1 contains positive residues that mediate membrane association and aid subsequent copper loading.
abstract: Copper chaperones bind intracellular copper and ensure proper trafficking to downstream targets via protein-protein interactions. In contrast to the mechanisms of copper binding and transfer to downstream targets, the mechanisms of initial copper loading of the chaperones are largely unknown. Here, we demonstrate that antioxidant protein 1 (Atox1 in human cells), the principal cellular copper chaperone responsible for delivery of copper to the secretory pathway, possesses the ability to interact with negatively charged lipid headgroups via distinct surface lysine residues. Moreover, loss of these residues lowers the efficiency of copper loading of Atox1 in vivo, suggesting that the membrane may play a scaffolding role in copper distribution to Atox1. These findings complement the recent discovery that the membrane also facilitates copper loading of the copper chaperone for superoxide dismutase 1 and provide further support for the emerging paradigm that the membrane bilayer plays a central role in cellular copper acquisition and distribution.
authors.affiliation: Department of Molecular Biosciences and Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA.
authors.forename: Adrian G
authors.initials: AG
authors.lastname: Flores
authors.forename: Vinzenz M
authors.initials: VM
authors.lastname: Unger
mesh_terms: D019943:Amino Acid Substitution; D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D000079922:Copper Transport Proteins; D006801:Humans; D056511:Metallochaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D018832:Molecular Chaperones; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: C474500:ATOX1 protein, human; D000596:Amino Acids; D000079922:Copper Transport Proteins; D056511:Metallochaperones; D018832:Molecular Chaperones; D003300:Copper
references.citation: J Biol Chem. 1998 Jan 16;273(3):1749-54
references.pmid: 9430722
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13363-8
references.pmid: 10557326
references.citation: Arch Biochem Biophys. 2008 Aug 1;476(1):22-32
references.pmid: 18534184
references.citation: Chem Commun (Camb). 2002 Mar 21;(6):588-9
references.pmid: 12120136
references.citation: J Biol Chem. 1999 May 21;274(21):15041-5
references.pmid: 10329707
references.citation: Am J Clin Nutr. 1998 May;67(5 Suppl):1069S-1073S
references.pmid: 9587154
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11158-63
references.pmid: 18685091
references.citation: J Am Chem Soc. 2011 Mar 9;133(9):2983-8
references.pmid: 21323310
references.citation: Chem Biol. 2002 Jun;9(6):673-7
references.pmid: 12079778
references.citation: Methods Enzymol. 1990;186:1-85
references.pmid: 2172697
references.citation: Genome Res. 2002 Feb;12(2):255-71
references.pmid: 11827945
references.citation: J Biol Chem. 2001 Nov 2;276(44):41365-76
references.pmid: 11500502
references.citation: Bioinorg Chem Appl. 2004;:105-23
references.pmid: 18365072
references.citation: J Biol Chem. 1994 Oct 14;269(41):25660-7
references.pmid: 7929270
references.citation: Biochemistry. 2001 Feb 13;40(6):1528-39
references.pmid: 11327811
references.citation: Nat Rev Mol Cell Biol. 2008 Feb;9(2):112-24
references.pmid: 18216768
references.citation: J Biol Chem. 1997 Apr 4;272(14):9221-6
references.pmid: 9083055
references.citation: Chem Rev. 2009 Oct;109(10):4760-79
references.pmid: 19824702
references.citation: Am J Physiol Cell Physiol. 2013 Apr 15;304(8):C768-79
references.pmid: 23426973
references.citation: Nat Chem Biol. 2008 Mar;4(3):176-85
references.pmid: 18277979
references.citation: Biochem J. 2004 Oct 15;383(Pt 2):303-9
references.pmid: 15239669
references.citation: Nat Chem Biol. 2006 Jul;2(7):367-8
references.pmid: 16732294
references.citation: FEBS Lett. 1998 Nov 27;440(1-2):141-6
references.pmid: 9862443
references.citation: Curr Opin Cell Biol. 2011 Aug;23(4):370-6
references.pmid: 21665455
references.citation: J Biol Chem. 1997 Apr 4;272(14):9215-20
references.pmid: 9083054
references.citation: J Cell Sci. 2011 Jan 1;124(Pt 1):5-8
references.pmid: 21172818
references.citation: Biochim Biophys Acta. 2011 Apr;1808(4):1092-102
references.pmid: 21167813
references.citation: J Biol Chem. 2000 Aug 18;275(33):25057-60
references.pmid: 10816601
references.citation: Future Med Chem. 2009 Sep;1(6):1125-42
references.pmid: 20454597
references.citation: Biochemistry. 2004 Oct 19;43(41):13046-53
references.pmid: 15476398
references.citation: Biochem J. 2009 Jul 29;422(1):37-42
references.pmid: 19453293
references.citation: EMBO J. 1996 Nov 15;15(22):6084-95
references.pmid: 8947031
references.citation: Front Biosci. 2004 Sep 01;9:2652-62
references.pmid: 15358588
references.citation: J Biol Chem. 2002 Aug 2;277(31):27953-9
references.pmid: 12029094
references.citation: J Biol Chem. 1999 Oct 1;274(40):28497-504
references.pmid: 10497213
references.citation: J Biol Chem. 1997 Aug 22;272(34):21461-6
references.pmid: 9261163
references.citation: Science. 1997 Oct 31;278(5339):853-6
references.pmid: 9346482
references.citation: Antioxid Redox Signal. 2013 Sep 20;19(9):945-57
references.pmid: 23249252
references.citation: J Biol Chem. 2000 Jun 23;275(25):18611-4
references.pmid: 10764731
references.citation: Plant Physiol. 1998 Aug;117(4):1227-34
references.pmid: 9701579
references.citation: Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3784-8
references.pmid: 7731983