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dc.contributor.authorBolduc, David M.
dc.contributor.authorMontagna, Daniel R.
dc.contributor.authorSeghers, Matthew C.
dc.contributor.authorWolfe, Michael Scott
dc.contributor.authorSelkoe, Dennis J.
dc.date.accessioned2017-09-22T19:09:21Z
dc.date.available2017-09-22T19:09:21Z
dc.date.issued2016-08-30
dc.identifier.citationBolduc, D. M., Montagna, D. R., Seghers, M. C., Wolfe, M. S., & Selkoe, D. J. (2016). The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase. eLife, 5, e17578. http://doi.org/10.7554/eLife.17578en_US
dc.identifier.urihttp://hdl.handle.net/1808/25007
dc.description.abstractγ-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.en_US
dc.publishereLife Sciences Publicationsen_US
dc.rightsThis article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleThe amyloid-beta forming tripeptide cleavage mechanism of γ-secretaseen_US
dc.typeArticleen_US
kusw.kuauthorWolfe, Michael Scott
kusw.kudepartmentMedicinal Chemistryen_US
dc.identifier.doi10.7554/eLife.17578en_US
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC5134833en_US
dc.rights.accessrightsopenAccess


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This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Except where otherwise noted, this item's license is described as: This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.