Molecular mechanism of substrate recognition and cleavage by human γ-secretase.
Science
; 384(6700): 1091-1095, 2024 Jun 07.
Article
in En
| MEDLINE
| ID: mdl-38843321
ABSTRACT
Successive cleavages of amyloid precursor protein C-terminal fragment with 99 residues (APP-C99) by γ-secretase result in amyloid-ß (Aß) 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, Aß49, Aß46, and Aß43. In all cases, the substrate displays the same structural features a transmembrane α-helix, a three-residue linker, and a ß-strand that forms a hybrid ß-sheet with presenilin 1 (PS1). Proteolytic cleavage occurs just ahead of the substrate ß-strand. Each cleavage is followed by unwinding and translocation of the substrate α-helix by one turn and the formation of a new ß-strand. This mechanism is consistent with existing biochemical data and may explain the cleavages of other substrates by γ-secretase.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Amyloid beta-Peptides
/
Amyloid beta-Protein Precursor
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Amyloid Precursor Protein Secretases
/
Presenilin-1
Limits:
Humans
Language:
En
Journal:
Science
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: