7E6P

Fab-amyloid beta fragment complex

7E6P の概要

• エントリーDOI: 10.2210/pdb7e6p/pdb
• 分子名称: Fab Heavy chain, Fab Light chain, Amyloid beta fragment with an intramolecular disulfide bond at positions 17 and 28, ... (6 entities in total)
• 機能のキーワード: fab complex, immune system
• 由来する生物種: Mus musculus; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 50181.82

構造登録者

Kita, A.,Irie, K.,Irie, Y.,Miki, K. (登録日: 2021-02-23, 公開日: 2022-01-05, 最終更新日: 2024-10-23)

主引用文献

Kageyama, Y.,Irie, Y.,Matsushima, Y.,Segawa, T.,Bellier, J.P.,Hidaka, K.,Sugiyama, H.,Kaneda, D.,Hashizume, Y.,Akatsu, H.,Miki, K.,Kita, A.,Walker, D.G.,Irie, K.,Tooyama, I.
Characterization of a Conformation-Restricted Amyloid beta Peptide and Immunoreactivity of Its Antibody in Human AD brain.
Acs Chem Neurosci, 12:3418-3432, 2021

PubMed Abstract: Characterization of amyloid β (Aβ) oligomers, the transition species present prior to the formation of Aβ fibrils and that have cytotoxicity, has become one of the major topics in the investigations of Alzheimer's disease (AD) pathogenesis. However, studying pathophysiological properties of Aβ oligomers is challenging due to the instability of these protein complexes . Here, we report that conformation-restricted Aβ42 with an intramolecular disulfide bond at positions 17 and 28 (SS-Aβ42) formed stable Aβ oligomers . Thioflavin T binding assays, nondenaturing gel electrophoresis, and morphological analyses revealed that SS-Aβ42 maintained oligomeric structure, whereas wild-type Aβ42 and the highly aggregative Aβ42 mutant with E22P substitution (E22P-Aβ42) formed Aβ fibrils. In agreement with these observations, SS-Aβ42 was more cytotoxic compared to the wild-type and E22P-Aβ42 in cell cultures. Furthermore, we developed a monoclonal antibody, designated TxCo-1, using the toxic conformation of SS-Aβ42 as immunogen. X-ray crystallography of the TxCo-1/SS-Aβ42 complex, enzyme immunoassay, and immunohistochemical studies confirmed the recognition site and specificity of TxCo-1 to SS-Aβ42. Immunohistochemistry with TxCo-1 antibody identified structures resembling senile plaques and vascular Aβ in brain samples of AD subjects. However, TxCo-1 immunoreactivity did not colocalize extensively with Aβ plaques identified with conventional Aβ antibodies. Together, these findings indicate that Aβ with a turn at positions 22 and 23, which is prone to form Aβ oligomers, could show strong cytotoxicity and accumulated in brains of AD subjects. The SS-Aβ42 and TxCo-1 antibody should facilitate understanding of the pathological role of Aβ with toxic conformation in AD.

PubMed: 34464082
DOI: 10.1021/acschemneuro.1c00416

実験手法

X-RAY DIFFRACTION (2.5 Å)