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

  • Henna Zahid
    ,
  • Layeque Miah
    ,
  • Andy M. Lau
    ,
  • Lea Brochard
    ,
  • Debolina Hati
    ,
  • Tam T.T. Bui
  • University College London
    ,
  • King's College London
Research Output: Contribution to journal Article Peer-review

Open access

Sustainable Development Goals

  • SDG 3 - Good Health and Well-being
    SDG 3 Good Health and Well

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.

Publication Information

Output type

Research Output: Contribution to journal Article Peer-review

Original language

English

Pages from-to (Number of pages)

Pages 43-54

Journal (Volume, Issue Number)

Biochemical Journal (Volume 473, Issue 1)

Publication milestones

  • Accepted/In press - 20/10/2015
  • Published - 09/12/2015

Publication status

Published - 09/12/2015

ISSN

0264-6021

External Publication IDs

  • handle.net: 10547/622302
  • Scopus: 84955450261

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