Identification of a novel tetrameric structure for human apolipoprotein-D
Research output: Contribution to journal › Journal article › Research › peer-review
Apolipoprotein-D is a 25 kDa glycosylated member of the lipocalin family that folds into an eight-stranded β-barrel with a single adjacent α-helix. Apolipoprotein-D specifically binds a range of small hydrophobic ligands such as progesterone and arachidonic acid and has an antioxidant function that is in part due to the reduction of peroxidised lipids by methionine-93. Therefore, apolipoprotein-D plays multiple roles throughout the body and is protective in Alzheimer's disease, where apolipoprotein-D overexpression reduces the amyloid-β burden in Alzheimer's disease mouse models. Oligomerisation is a common feature of lipocalins that can influence ligand binding. The native structure of apolipoprotein-D, however, has not been conclusively defined. Apolipoprotein-D is generally described as a monomeric protein, although it dimerises when reducing peroxidised lipids. Here, we investigated the native structure of apolipoprotein-D derived from plasma, breast cyst fluid (BCF) and cerebrospinal fluid. In plasma and cerebrospinal fluid, apolipoprotein-D was present in high-molecular weight complexes, potentially in association with lipoproteins. In contrast, apolipoprotein-D in BCF formed distinct oligomeric species. We assessed apolipoprotein-D oligomerisation using native apolipoprotein-D purified from BCF and a suite of complementary methods, including multi-angle laser light scattering, analytical ultracentrifugation and small-angle X-ray scattering. Our analyses showed that apolipoprotein-D predominantly forms a ∼95 to ∼100 kDa tetramer. Small-angle X-ray scattering analysis confirmed these findings and provided a structural model for apolipoprotein-D tetramer. These data indicate apolipoprotein-D rarely exists as a free monomer under physiological conditions and provide insights into novel native structures of apolipoprotein-D and into oligomerisation behaviour in the lipocalin family.
Original language | English |
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Journal | Journal of Structural Biology |
Volume | 203 |
Issue number | 3 |
Pages (from-to) | 205-218 |
Number of pages | 14 |
ISSN | 1047-8477 |
DOIs | |
Publication status | Published - Sep 2018 |
Externally published | Yes |
Bibliographical note
Copyright © 2018 Elsevier Inc. All rights reserved.
- Alzheimer Disease/genetics, Amyloid beta-Peptides/chemistry, Animals, Apolipoproteins D/cerebrospinal fluid, Breast Cyst/chemistry, Crystallography, X-Ray, Disease Models, Animal, Humans, Ligands, Lipocalins/chemistry, Mice, Protein Binding, Protein Conformation, Protein Multimerization, Scattering, Small Angle
Research areas
ID: 285315277