Identification of a novel tetrameric structure for human apolipoprotein-D
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Identification of a novel tetrameric structure for human apolipoprotein-D. / Kielkopf, Claudia S; Low, Jason K K; Mok, Yee-Foong; Bhatia, Surabhi; Palasovski, Tony; Oakley, Aaron J; Whitten, Andrew E; Garner, Brett; Brown, Simon H J.
In: Journal of Structural Biology, Vol. 203, No. 3, 09.2018, p. 205-218.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Identification of a novel tetrameric structure for human apolipoprotein-D
AU - Kielkopf, Claudia S
AU - Low, Jason K K
AU - Mok, Yee-Foong
AU - Bhatia, Surabhi
AU - Palasovski, Tony
AU - Oakley, Aaron J
AU - Whitten, Andrew E
AU - Garner, Brett
AU - Brown, Simon H J
N1 - Copyright © 2018 Elsevier Inc. All rights reserved.
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
KW - Alzheimer Disease/genetics
KW - Amyloid beta-Peptides/chemistry
KW - Animals
KW - Apolipoproteins D/cerebrospinal fluid
KW - Breast Cyst/chemistry
KW - Crystallography, X-Ray
KW - Disease Models, Animal
KW - Humans
KW - Ligands
KW - Lipocalins/chemistry
KW - Mice
KW - Protein Binding
KW - Protein Conformation
KW - Protein Multimerization
KW - Scattering, Small Angle
U2 - 10.1016/j.jsb.2018.05.012
DO - 10.1016/j.jsb.2018.05.012
M3 - Journal article
C2 - 29885491
VL - 203
SP - 205
EP - 218
JO - Journal of Structural Biology
JF - Journal of Structural Biology
SN - 1047-8477
IS - 3
ER -
ID: 285315277