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

DOI: 10.1042/BCJ20190354 DOI Help

Authors: Andy M. Lau (University College London (UCL)) , Henna Zahid (University College London (UCL)) , Jayesh Gor (University College London) , Stephen J. Perkins (University College London (UCL)) , Alun R. Coker (University College Medical School, UCL Divisision of Medicine) , Lindsay C Mcdermott (University of Bedfordshire)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemical Journal

State: Published (Approved)
Published: September 2019
Diamond Proposal Number(s): 12342

Open Access Open Access

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.

Journal Keywords: Analytical ultracentrifugation; DAUDA; fluorescence; obesity; x-ray crystallography

Subject Areas: Chemistry, Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography