8X54
Cryo-EM structure of human gamma-secretase in complex with APP-C99
Summary for 8X54
| Entry DOI | 10.2210/pdb8x54/pdb |
| EMDB information | 38061 |
| Descriptor | Amyloid-beta precursor protein, CHOLESTEROL, Nicastrin, ... (10 entities in total) |
| Functional Keywords | intramembrane protease, gamma-secretase, presenilin-1, membrane protein, membrane protein-hydrolase complex |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 193949.18 |
| Authors | |
| Primary citation | 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 Cited by 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: 38843321DOI: 10.1126/science.adn5820 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.9 Å) |
Structure validation
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