The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase

The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase

γ-secretase is responsible for the proteolysis of amyloid precursor protein (APP) into short, aggregation-prone amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer’s disease (AD). Despite considerable interest in developing γ-secretase targeting therapeutics f...

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Main Authors: Bolduc, David M, Montagna, Daniel R, Seghers, Matthew C, Wolfe, Michael S, Selkoe, Dennis J
Format: Online
Language:English
Published: eLife Sciences Publications, Ltd 2016
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134833/
id pubmed-5134833
recordtype oai_dc
spelling pubmed-51348332016-12-05 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 Biochemistry γ-secretase is responsible for the proteolysis of amyloid precursor protein (APP) into short, aggregation-prone amyloid-beta (Aβ) 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 Aβ 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 Aβ species. eLife Sciences Publications, Ltd 2016-08-31 /pmc/articles/PMC5134833/ /pubmed/27580372 http://dx.doi.org/10.7554/eLife.17578 Text en © 2016, Bolduc et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Bolduc, David M
Montagna, Daniel R
Seghers, Matthew C
Wolfe, Michael S
Selkoe, Dennis J
spellingShingle Bolduc, David M
Montagna, Daniel R
Seghers, Matthew C
Wolfe, Michael S
Selkoe, Dennis J
The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase
author_facet Bolduc, David M
Montagna, Daniel R
Seghers, Matthew C
Wolfe, Michael S
Selkoe, Dennis J
author_sort Bolduc, David M
title The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase
title_short The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase
title_full The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase
title_fullStr The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase
title_full_unstemmed The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase
title_sort amyloid-beta forming tripeptide cleavage mechanism of γ-secretase
description γ-secretase is responsible for the proteolysis of amyloid precursor protein (APP) into short, aggregation-prone amyloid-beta (Aβ) 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 Aβ 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 Aβ species.
publisher eLife Sciences Publications, Ltd
publishDate 2016
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134833/
_version_ 1613754356741439488

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