8VXJ

The crystal structure of human apolipoprotein A-I in complex with Fab 55201

8VXJ の概要

• エントリーDOI: 10.2210/pdb8vxj/pdb
• 分子名称: Apolipoprotein A-I, Fab 55201 heavy chain, Fab 55201 light chain, ... (4 entities in total)
• 機能のキーワード: hdl, apolipoprotein, lipid binding, plasma, lipid transport, lipid transport-immune system complex, lipid transport/immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 147690.26

構造登録者

Tou, H.I.,Metcalfe, R.D.,Khandokar, Y.,Griffin, M.D.W. (登録日: 2024-02-04, 公開日: 2025-08-27, 最終更新日: 2025-09-17)

主引用文献

Tou, H.I.,Rosenes, Z.,Khandokar, Y.,Zlatic, C.O.,Metcalfe, R.D.,Mok, Y.F.,Morton, C.J.,Gooley, P.R.,Griffin, M.D.W.
The Structure of the Apolipoprotein A-I Monomer Provides Insights Into Its Oligomerisation and Lipid-binding Mechanisms.
J.Mol.Biol., 437:169394-169394, 2025

PubMed Abstract: Apolipoprotein A-I (apoA-I) plays important roles in clearing cholesterol and phospholipids from peripheral tissues, forming high-density lipoprotein (HDL). However, despite this important function, apoA-I has a propensity to form amyloid fibrils implicated in atherosclerosis and hereditary amyloidosis. Historically, structural determination of lipid-free or lipid-poor apoA-I has been difficult. Here, we obtained the crystal structure of the apoA-I monomer in complex with the antigen-binding fragment (Fab) of a monoclonal antibody. The structure reveals that the N-terminal domain (NTD, residues 1-184) of apoA-I is a compact four-helical bundle, whereas the C-terminal domain (CTD, residues 185-243) is unresolved in the structure. Molecular Dynamics (MD) simulations and small-angle X-ray scattering (SAXS) analysis revealed that the apoA-I NTD dimerises by domain-swapping and the dimer is elongated. Methionine (Met) oxidation in apoA-I destabilises both full-length apoA-I (apoA-I) and C-terminally truncated apoA-I (apoA-I), causing dissociation of the domain-swapped dimer and fibril formation. Met oxidation also increased the lipid-binding ability of apoA-I, while the amyloidogenic mutation, G26R, did not. Hydrogen-deuterium exchange coupled with nuclear magnetic resonance (HDX-NMR), SAXS, and MD analyses showed that triply Met-oxidised (3MetO) and G26R apoA-I are both highly dynamic but remain partially folded. Based on these results, we propose that domain-swapping dimerisation also exists in apoA-I, with the CTD mediating further oligomerisation. We also propose that lipid-binding is promoted by increased global destabilisation in the protein structure, and/or driven by a specific local conformation that is induced by Met-oxidation but not the G26R mutation.

PubMed: 40816717
DOI: 10.1016/j.jmb.2025.169394

実験手法

X-RAY DIFFRACTION (2.7 Å)