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dc.contributor.authorLiu, Lei
dc.contributor.authorDing, Li
dc.contributor.authorRovere, Matteo
dc.contributor.authorWolfe, Michael S.
dc.contributor.authorSelkoe, Dennis J.
dc.identifier.citationLei Liu, Li Ding, Matteo Rovere, Michael S. Wolfe, Dennis J. Selkoe; A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor. J Cell Biol 4 February 2019; 218 (2): 644–663. doi:
dc.descriptionThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.en_US
dc.description.abstractIntramembrane proteolysis of transmembrane substrates by the presenilin–γ-secretase complex is preceded and regulated by shedding of the substrate’s ectodomain by α- or β-secretase. We asked whether β- and γ-secretases interact to mediate efficient sequential processing of APP, generating the amyloid β (Aβ) peptides that initiate Alzheimer’s disease. We describe a hitherto unrecognized multiprotease complex containing active β- and γ-secretases. BACE1 coimmunoprecipitated and cofractionated with γ-secretase in cultured cells and in mouse and human brain. An endogenous high molecular weight (HMW) complex (∼5 MD) containing β- and γ-secretases and holo-APP was catalytically active in vitro and generated a full array of Aβ peptides, with physiological Aβ42/40 ratios. The isolated complex responded properly to γ-secretase modulators. Alzheimer’s-causing mutations in presenilin altered the Aβ42/40 peptide ratio generated by the HMW β/γ-secretase complex indistinguishably from that observed in whole cells. Thus, Aβ is generated from holo-APP by a BACE1–γ-secretase complex that provides sequential, efficient RIP processing of full-length substrates to final products.en_US
dc.publisherRockefeller University Pressen_US
dc.rights© 2019 Liu et al.en_US
dc.subjectProtein homeostasisen_US
dc.titleA cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursoren_US
kusw.kuauthorWolfe, Michael S.
kusw.kudepartmentMedicinal Chemistryen_US
kusw.oanotesPer Sherpa Romeo 01/18/2021:

Journal of Cell Biology [Open panel below]Publication Information TitleJournal of Cell Biology [English] ISSNs Print: 0021-9525 Electronic: 1540-8140 URL PublishersRockefeller University Press [University Publisher] [Open panel below]Publisher Policy Open Access pathways permitted by this journal's policy are listed below by article version. Click on a pathway for a more detailed view.

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kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

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© 2019 Liu et al.
Except where otherwise noted, this item's license is described as: © 2019 Liu et al.