Zinc-induced oligomerisation of zinc α2 glycoprotein reveals multiple fatty acid binding sites

2.50
Hdl Handle:
http://hdl.handle.net/10547/622302
Title:
Zinc-induced oligomerisation of zinc α2 glycoprotein reveals multiple fatty acid binding sites
Authors:
Zahid, Henna; Miah, Layeque; Lau, Andy M.; Brochard, Lea; Hati, Debolina; Bui, Tam T. T.; Drake, Alex F.; Gor, Jayesh; Perkins, Stephen J.; McDermott, Lindsay C.
Other Titles:
Zinc-induced oligomerization of zinc α2 glycoprotein
Abstract:
Zinc α2 glycoprotein (ZAG) is an adipokine with a class I major histocompatibility complex protein fold and is associated with obesity and diabetes. Although its intrinsic ligand remains unknown, ZAG binds the dansylated C11 fatty acid, DAUDA, in the groove between the α1 and α2 domains. The surface of ZAG has about 15 weak zinc binding sites deemed responsible for precipitation from human plasma. Here the functional significance of these metal sites was investigated. Analytical ultracentrifugation and circular dichroism showed that zinc, but not other divalent metals, cause ZAG to oligomerise in solution. Thus ZAG dimers and trimers were observed in the presence of 1 mM and 2 mM zinc. Molecular modelling of X-ray scattering curves and sedimentation coefficients indicated a progressive stacking of ZAG monomers, suggesting the ZAG groove may be occluded in these. Using fluorescence-detected sedimentation velocity, these ZAG-zinc oligomers were again observed in the presence of the fluorescent boron dipyrromethene fatty acid C16-BODIPY. Fluorescence spectroscopy confirmed that ZAG binds C16-BODIPY. ZAG binding to C16-BODIPY, but not to DAUDA, was reduced by increased zinc concentrations. We conclude that the lipid binding groove in ZAG contains at least two distinct fatty acid binding sites for DAUDA and C16-BODIPY, similar to the multiple lipid binding seen in the structurally-related immune protein Cd1c. In addition, because high concentrations of zinc occur in the pancreas, the perturbation of these multiple lipid binding sites by zinc may be significant in Type 2 diabetes where dysregulation of ZAG and zinc homeostasis occurs.
Affiliation:
King's College London; University College London; University of Bedfordshire
Citation:
Zahid H, Miah L, Lau AM, Brochard L, Hati D, Bui TTT, Drake AF, Gor J, Perkins SJ, McDermott LC (2015) 'Zinc-induced oligomerisation of zinc α2 glycoprotein reveals multiple fatty acid binding sites', Biochemical Journal, 473, pp.43-54.
Publisher:
Portland Press
Journal:
Biochemical Journal
Issue Date:
9-Dec-2015
URI:
http://hdl.handle.net/10547/622302
DOI:
doi:10.1042/BJ20150836
Additional Links:
http://www.biochemj.org/content/473/1/43.article-info
Type:
Article
Language:
en
ISSN:
0264-6021
Sponsors:
This work was supported by the Collaborative Computational Project for advanced analyses of structural data in chemical biology and soft condensed matter (CCPSAS), a joint Engineering and Physical Sciences Research Council (EPSRC) [grant number EP/K039121/1]; and the National Science Foundation (NSF) [grant number CHE- 1265821].
Appears in Collections:
Biomedical and biological science

Full metadata record

DC FieldValue Language
dc.contributor.authorZahid, Hennaen
dc.contributor.authorMiah, Layequeen
dc.contributor.authorLau, Andy M.en
dc.contributor.authorBrochard, Leaen
dc.contributor.authorHati, Debolinaen
dc.contributor.authorBui, Tam T. T.en
dc.contributor.authorDrake, Alex F.en
dc.contributor.authorGor, Jayeshen
dc.contributor.authorPerkins, Stephen J.en
dc.contributor.authorMcDermott, Lindsay C.en
dc.date.accessioned2017-10-19T09:13:08Z-
dc.date.available2017-10-19T09:13:08Z-
dc.date.issued2015-12-09-
dc.identifier.citationZahid H, Miah L, Lau AM, Brochard L, Hati D, Bui TTT, Drake AF, Gor J, Perkins SJ, McDermott LC (2015) 'Zinc-induced oligomerisation of zinc α2 glycoprotein reveals multiple fatty acid binding sites', Biochemical Journal, 473, pp.43-54.en
dc.identifier.issn0264-6021-
dc.identifier.doidoi:10.1042/BJ20150836-
dc.identifier.urihttp://hdl.handle.net/10547/622302-
dc.description.abstractZinc α2 glycoprotein (ZAG) is an adipokine with a class I major histocompatibility complex protein fold and is associated with obesity and diabetes. Although its intrinsic ligand remains unknown, ZAG binds the dansylated C11 fatty acid, DAUDA, in the groove between the α1 and α2 domains. The surface of ZAG has about 15 weak zinc binding sites deemed responsible for precipitation from human plasma. Here the functional significance of these metal sites was investigated. Analytical ultracentrifugation and circular dichroism showed that zinc, but not other divalent metals, cause ZAG to oligomerise in solution. Thus ZAG dimers and trimers were observed in the presence of 1 mM and 2 mM zinc. Molecular modelling of X-ray scattering curves and sedimentation coefficients indicated a progressive stacking of ZAG monomers, suggesting the ZAG groove may be occluded in these. Using fluorescence-detected sedimentation velocity, these ZAG-zinc oligomers were again observed in the presence of the fluorescent boron dipyrromethene fatty acid C16-BODIPY. Fluorescence spectroscopy confirmed that ZAG binds C16-BODIPY. ZAG binding to C16-BODIPY, but not to DAUDA, was reduced by increased zinc concentrations. We conclude that the lipid binding groove in ZAG contains at least two distinct fatty acid binding sites for DAUDA and C16-BODIPY, similar to the multiple lipid binding seen in the structurally-related immune protein Cd1c. In addition, because high concentrations of zinc occur in the pancreas, the perturbation of these multiple lipid binding sites by zinc may be significant in Type 2 diabetes where dysregulation of ZAG and zinc homeostasis occurs.en
dc.description.sponsorshipThis work was supported by the Collaborative Computational Project for advanced analyses of structural data in chemical biology and soft condensed matter (CCPSAS), a joint Engineering and Physical Sciences Research Council (EPSRC) [grant number EP/K039121/1]; and the National Science Foundation (NSF) [grant number CHE- 1265821].en
dc.language.isoenen
dc.publisherPortland Pressen
dc.relation.urlhttp://www.biochemj.org/content/473/1/43.article-infoen
dc.rightsWhite - archiving not formally supported-
dc.subjectadiposityen
dc.subjectzincen
dc.titleZinc-induced oligomerisation of zinc α2 glycoprotein reveals multiple fatty acid binding sitesen
dc.title.alternativeZinc-induced oligomerization of zinc α2 glycoproteinen
dc.typeArticleen
dc.contributor.departmentKing's College Londonen
dc.contributor.departmentUniversity College Londonen
dc.contributor.departmentUniversity of Bedfordshireen
dc.identifier.journalBiochemical Journalen
dc.date.updated2017-10-19T09:03:23Z-
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