Crystal structure of zinc-α2-glycoprotein in complex with a fatty acid reveals multiple different modes of protein-lipid binding
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Issue Date
2019-10-11Subjects
n-3 polyunsaturated fatty acidsobesity
analytical ultracentrifugation
DAUDA
fluorescence
x-ray crystallography
C700 Molecular Biology, Biophysics and Biochemistry
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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.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, 476 (19), pp.2815-2834.Publisher
Portland PressJournal
Biochemical JournalPubMed ID
31506272Additional Links
http://www.biochemj.org/content/early/2019/09/10/BCJ20190354Type
ArticleLanguage
enISSN
0264-6021Sponsors
BBSRC LIDO PhD studentship awards [grant number BB/M009513/1]ae974a485f413a2113503eed53cd6c53
10.1042/BCJ20190354
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