8X54

Cryo-EM structure of human gamma-secretase in complex with APP-C99

8X54 の概要

• エントリーDOI: 10.2210/pdb8x54/pdb
• EMDBエントリー: 38061
• 分子名称: Amyloid-beta precursor protein, CHOLESTEROL, Nicastrin, ... (10 entities in total)
• 機能のキーワード: intramembrane protease, gamma-secretase, presenilin-1, membrane protein, membrane protein-hydrolase complex
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 193949.18

構造登録者

Guo, X.,Yan, C.,Lei, J.,Zhou, R.,Shi, Y. (登録日: 2023-11-16, 公開日: 2024-05-29, 最終更新日: 2025-07-16)

主引用文献

Guo, X.,Li, H.,Yan, C.,Lei, J.,Zhou, R.,Shi, Y.
Molecular mechanism of substrate recognition and cleavage by human gamma-secretase.
Science, 384:1091-1095, 2024

PubMed Abstract: Successive cleavages of amyloid precursor protein C-terminal fragment with 99 residues (APP-C99) by γ-secretase result in amyloid-β (Aβ) peptides of varying lengths. Most cleavages have a step size of three residues. To elucidate the underlying mechanism, we determined the atomic structures of human γ-secretase bound individually to APP-C99, Aβ49, Aβ46, and Aβ43. In all cases, the substrate displays the same structural features: a transmembrane α-helix, a three-residue linker, and a β-strand that forms a hybrid β-sheet with presenilin 1 (PS1). Proteolytic cleavage occurs just ahead of the substrate β-strand. Each cleavage is followed by unwinding and translocation of the substrate α-helix by one turn and the formation of a new β-strand. This mechanism is consistent with existing biochemical data and may explain the cleavages of other substrates by γ-secretase.

PubMed: 38843321
DOI: 10.1126/science.adn5820

実験手法

ELECTRON MICROSCOPY (2.9 Å)