| Structural highlights
Function
[QSOX1_HUMAN] Catalyzes the oxidation of sulfhydryl groups in peptide and protein thiols to disulfides with the reduction of oxygen to hydrogen peroxide. May contribute to disulfide bond formation in a variety of secreted proteins. In fibroblasts, it may have tumor-suppressing capabilities being involved in growth regulation.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Quiescin sulfhydryl oxidase 1 (QSOX1) is a catalyst of disulfide bond formation that undergoes regulated secretion from fibroblasts and is over-produced in adenocarcinomas and other cancers. We have recently shown that QSOX1 is required for incorporation of particular laminin isoforms into the extracellular matrix (ECM) of cultured fibroblasts and, as a consequence, for tumor cell adhesion to and penetration of the ECM. The known role of laminins in integrin-mediated cell survival and motility suggests that controlling QSOX1 activity may provide a novel means of combating metastatic disease. With this motivation, we developed a monoclonal antibody that inhibits the activity of human QSOX1. Here, we present the biochemical and structural characterization of this antibody and demonstrate that it is a tight-binding inhibitor that blocks one of the redox-active sites in the enzyme, but not the site at which de novo disulfides are generated catalytically. Sulfhydryl oxidase activity is thus prevented without direct binding of the sulfhydryl oxidase domain, confirming the model for the interdomain QSOX1 electron transfer mechanism originally surmised based on mutagenesis and protein dissection. In addition, we developed a single-chain variant of the antibody and show that it is a potent QSOX1 inhibitor. The QSOX1 inhibitory antibody will be a valuable tool in studying the role of ECM composition and architecture in cell migration, and the recombinant version may be further developed for potential therapeutic applications based on manipulation of the tumor microenvironment.
An Inhibitory Antibody Blocks the First Step in the Dithiol/Disulfide Relay Mechanism of the Enzyme QSOX1.,Grossman I, Alon A, Ilani T, Fass D J Mol Biol. 2013 Nov 15;425(22):4366-78. doi: 10.1016/j.jmb.2013.07.011. Epub, 2013 Jul 15. PMID:23867277[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Radom J, Colin D, Thiebault F, Dognin-Bergeret M, Mairet-Coello G, Esnard-Feve A, Fellmann D, Jouvenot M. Identification and expression of a new splicing variant of FAD-sulfhydryl oxidase in adult rat brain. Biochim Biophys Acta. 2006 May;1759(5):225-33. Epub 2006 May 9. PMID:16806532 doi:http://dx.doi.org/10.1016/j.bbaexp.2006.04.008
- ↑ Hoober KL, Glynn NM, Burnside J, Coppock DL, Thorpe C. Homology between egg white sulfhydryl oxidase and quiescin Q6 defines a new class of flavin-linked sulfhydryl oxidases. J Biol Chem. 1999 Nov 5;274(45):31759-62. PMID:10542195
- ↑ Coppock D, Kopman C, Gudas J, Cina-Poppe DA. Regulation of the quiescence-induced genes: quiescin Q6, decorin, and ribosomal protein S29. Biochem Biophys Res Commun. 2000 Mar 16;269(2):604-10. PMID:10708601 doi:http://dx.doi.org/10.1006/bbrc.2000.2324
- ↑ Thorpe C, Hoober KL, Raje S, Glynn NM, Burnside J, Turi GK, Coppock DL. Sulfhydryl oxidases: emerging catalysts of protein disulfide bond formation in eukaryotes. Arch Biochem Biophys. 2002 Sep 1;405(1):1-12. PMID:12176051
- ↑ Chakravarthi S, Jessop CE, Willer M, Stirling CJ, Bulleid NJ. Intracellular catalysis of disulfide bond formation by the human sulfhydryl oxidase, QSOX1. Biochem J. 2007 Jun 15;404(3):403-11. PMID:17331072 doi:http://dx.doi.org/10.1042/BJ20061510
- ↑ Heckler EJ, Alon A, Fass D, Thorpe C. Human quiescin-sulfhydryl oxidase, QSOX1: probing internal redox steps by mutagenesis. Biochemistry. 2008 Apr 29;47(17):4955-63. doi: 10.1021/bi702522q. Epub 2008 Apr, 5. PMID:18393449 doi:http://dx.doi.org/10.1021/bi702522q
- ↑ Grossman I, Alon A, Ilani T, Fass D. An Inhibitory Antibody Blocks the First Step in the Dithiol/Disulfide Relay Mechanism of the Enzyme QSOX1. J Mol Biol. 2013 Nov 15;425(22):4366-78. doi: 10.1016/j.jmb.2013.07.011. Epub, 2013 Jul 15. PMID:23867277 doi:http://dx.doi.org/10.1016/j.jmb.2013.07.011
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