+検索条件
-Structure paper
タイトル | Molecular mechanism of substrate recognition and cleavage by human γ-secretase. |
---|---|
ジャーナル・号・ページ | Science, Vol. 384, Issue 6700, Page 1091-1095, Year 2024 |
掲載日 | 2024年6月7日 |
著者 | Xuefei Guo / Haotian Li / Chuangye Yan / Jianlin Lei / Rui Zhou / Yigong Shi / |
PubMed 要旨 | 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 ...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. |
リンク | Science / PubMed:38843321 |
手法 | EM (単粒子) |
解像度 | 2.9 - 4.5 Å |
構造データ | EMDB-38059, PDB-8x52: EMDB-38060, PDB-8x53: EMDB-38061, PDB-8x54: EMDB-39574: Cryo-EM structure of human gamma-secretase in complex with Abeta43 |
化合物 | ChemComp-NAG: ChemComp-PC1: ChemComp-CLR: |
由来 |
|
キーワード | MEMBRANE PROTEIN / Intramembrane protease / gamma-secretase / presenilin-1 / MEMBRANE PROTEIN-HYDROLASE complex |