Your browser doesn't support javascript.
loading
The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase.
Bolduc, David M; Montagna, Daniel R; Seghers, Matthew C; Wolfe, Michael S; Selkoe, Dennis J.
Affiliation
  • Bolduc DM; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
  • Montagna DR; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
  • Seghers MC; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
  • Wolfe MS; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
  • Selkoe DJ; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
Elife ; 52016 08 31.
Article in En | MEDLINE | ID: mdl-27580372
γ-secretase is responsible for the proteolysis of amyloid precursor protein (APP) into short, aggregation-prone amyloid-beta (Aß) peptides, which are centrally implicated in the pathogenesis of Alzheimer's disease (AD). Despite considerable interest in developing γ-secretase targeting therapeutics for the treatment of AD, the precise mechanism by which γ-secretase produces Aß has remained elusive. Herein, we demonstrate that γ-secretase catalysis is driven by the stabilization of an enzyme-substrate scission complex via three distinct amino-acid-binding pockets in the enzyme's active site, providing the mechanism by which γ-secretase preferentially cleaves APP in three amino acid increments. Substrate occupancy of these three pockets occurs after initial substrate binding but precedes catalysis, suggesting a conformational change in substrate may be required for cleavage. We uncover and exploit substrate cleavage preferences dictated by these three pockets to investigate the mechanism by which familial Alzheimer's disease mutations within APP increase the production of pathogenic Aß species.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Amyloid beta-Peptides / Amyloid beta-Protein Precursor / Amyloid Precursor Protein Secretases / Proteolysis Limits: Humans Language: En Journal: Elife Year: 2016 Document type: Article Affiliation country: United States Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Amyloid beta-Peptides / Amyloid beta-Protein Precursor / Amyloid Precursor Protein Secretases / Proteolysis Limits: Humans Language: En Journal: Elife Year: 2016 Document type: Article Affiliation country: United States Country of publication: United kingdom