Crystal structure of zinc-α2-glycoprotein in complex with a fatty acid reveals multiple different modes of protein-lipid binding

2.50
Hdl Handle:
http://hdl.handle.net/10547/623430
Title:
Crystal structure of zinc-α2-glycoprotein in complex with a fatty acid reveals multiple different modes of protein-lipid binding
Authors:
Lau, Andy M.; Zahid, Henna; Gor, Jayesh; Perkins, Stephen J. ( 0000-0001-9218-9805 ) ; Coker, Alun R. ( 0000-0001-7385-0143 ) ; McDermott, Lindsay C. ( 0000-0003-4723-6056 )
Abstract:
Human zinc-α2-glycoprotein (ZAG) is a 42 kDa adipokine which regulates body fat mass and is associated with cachexia and obesity. ZAG belongs to the major histocompatibility complex class I protein family and binds long chain polyunsaturated fatty acids in its groove formed from the α1 and α2 domains. To identify the molecular basis of its lipid-binding function, we determined the first crystal structure at 2.49Å resolution for fatty acid-bound ZAG, where the ligand was the fluorescent 11-(dansylamino)undecanoic acid (DAUDA). The 192 kDa crystallographic asymmetric unit contained six ZAG and eight fatty acid molecules in unique conformations. Six fatty acid molecules were localised to the ZAG grooves, where its tails were bound in two distinct conformations. The carboxylate groups of three fatty acids projected out of the groove, while the fourth was hydrogen bonded with R73 inside the groove. Other ligand-residue contacts were primarily hydrophobic. A new fatty acid site was revealed for two further DAUDA molecules at the ZAG α3 domains. Following conformational changes from unbound ZAG, the α3 domains formed tetrameric β-barrel structures lined by fatty acid molecules that doubled the binding capacity of ZAG. Analytical ultracentrifugation revealed that ZAG in solution was a monomer in the absence of DAUDA, but formed small amounts of tetramers with DAUDA. By showing that ZAG binds fatty acids in different locations, we demonstrate an augmented mechanism for fatty acid binding in ZAG that is distinct from other known fatty acid binding proteins, and may be relevant to cachexia.
Affiliation:
University College London; University of Bedfordshire
Citation:
Lau AM, Zahid H, Gor J, Perkins SJ, Coker AR, McDermott LC (2019) 'Crystal structure of zinc-α2-glycoprotein in complex with a fatty acid reveals multiple different modes of protein-lipid binding', Biochemical Journal, (), pp.-.
Publisher:
Portland Press
Journal:
Biochemical Journal
Issue Date:
10-Sep-2019
URI:
http://hdl.handle.net/10547/623430
Type:
Article
Language:
en
ISSN:
0264-6021
Sponsors:
BBSRC LIDO PhD studentship awards [grant number BB/M009513/1]
Appears in Collections:
Biomedical and biological science

Full metadata record

DC FieldValue Language
dc.contributor.authorLau, Andy M.en
dc.contributor.authorZahid, Hennaen
dc.contributor.authorGor, Jayeshen
dc.contributor.authorPerkins, Stephen J.en
dc.contributor.authorCoker, Alun R.en
dc.contributor.authorMcDermott, Lindsay C.en
dc.date.accessioned2019-09-10T11:07:23Z-
dc.date.available2019-09-10T11:07:23Z-
dc.date.issued2019-09-10-
dc.identifier.citationLau AM, Zahid H, Gor J, Perkins SJ, Coker AR, McDermott LC (2019) 'Crystal structure of zinc-α2-glycoprotein in complex with a fatty acid reveals multiple different modes of protein-lipid binding', Biochemical Journal, (), pp.-.en
dc.identifier.issn0264-6021-
dc.identifier.urihttp://hdl.handle.net/10547/623430-
dc.description.abstractHuman zinc-α2-glycoprotein (ZAG) is a 42 kDa adipokine which regulates body fat mass and is associated with cachexia and obesity. ZAG belongs to the major histocompatibility complex class I protein family and binds long chain polyunsaturated fatty acids in its groove formed from the α1 and α2 domains. To identify the molecular basis of its lipid-binding function, we determined the first crystal structure at 2.49Å resolution for fatty acid-bound ZAG, where the ligand was the fluorescent 11-(dansylamino)undecanoic acid (DAUDA). The 192 kDa crystallographic asymmetric unit contained six ZAG and eight fatty acid molecules in unique conformations. Six fatty acid molecules were localised to the ZAG grooves, where its tails were bound in two distinct conformations. The carboxylate groups of three fatty acids projected out of the groove, while the fourth was hydrogen bonded with R73 inside the groove. Other ligand-residue contacts were primarily hydrophobic. A new fatty acid site was revealed for two further DAUDA molecules at the ZAG α3 domains. Following conformational changes from unbound ZAG, the α3 domains formed tetrameric β-barrel structures lined by fatty acid molecules that doubled the binding capacity of ZAG. Analytical ultracentrifugation revealed that ZAG in solution was a monomer in the absence of DAUDA, but formed small amounts of tetramers with DAUDA. By showing that ZAG binds fatty acids in different locations, we demonstrate an augmented mechanism for fatty acid binding in ZAG that is distinct from other known fatty acid binding proteins, and may be relevant to cachexia.en
dc.description.sponsorshipBBSRC LIDO PhD studentship awards [grant number BB/M009513/1]en
dc.language.isoenen
dc.publisherPortland Pressen
dc.rightsWhite - archiving not formally supported-
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectn-3 polyunsaturated fatty acidsen
dc.subjectobesityen
dc.subjectanalytical ultracentrifugationen
dc.subjectDAUDAen
dc.subjectfluorescenceen
dc.subjectx-ray crystallographyen
dc.subjectC700 Molecular Biology, Biophysics and Biochemistryen
dc.titleCrystal structure of zinc-α2-glycoprotein in complex with a fatty acid reveals multiple different modes of protein-lipid bindingen
dc.typeArticleen
dc.contributor.departmentUniversity College Londonen
dc.contributor.departmentUniversity of Bedfordshireen
dc.identifier.journalBiochemical Journalen
dc.date.updated2019-09-10T11:02:50Z-
dc.description.note12m embargo-
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