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TitleMolecular mechanism of substrate recognition and cleavage by human γ-secretase.
Journal, issue, pagesScience, Vol. 384, Issue 6700, Page 1091-1095, Year 2024
Publish dateJun 7, 2024
AuthorsXuefei Guo / Haotian Li / Chuangye Yan / Jianlin Lei / Rui Zhou / Yigong Shi /
PubMed AbstractSuccessive 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.
External linksScience / PubMed:38843321
MethodsEM (single particle)
Resolution2.9 - 4.5 Å
Structure data

38059

8x52

EMDB-38059, PDB-8x52:
Cryo-EM structure of human gamma-secretase in complex with Abeta49
Method: EM (single particle) / Resolution: 2.9 Å

38060

8x53

EMDB-38060, PDB-8x53:
Cryo-EM structure of human gamma-secretase in complex with Abeta46
Method: EM (single particle) / Resolution: 3.0 Å

38061

8x54

EMDB-38061, PDB-8x54:
Cryo-EM structure of human gamma-secretase in complex with APP-C99
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-39574: Cryo-EM structure of human gamma-secretase in complex with Abeta43
Method: EM (single particle) / Resolution: 4.5 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM / Phosphatidylcholine

ChemComp-CLR:
CHOLESTEROL / Cholesterol

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / Intramembrane protease / gamma-secretase / presenilin-1 / MEMBRANE PROTEIN-HYDROLASE complex

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