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A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor
dc.contributor.author | Liu, Lei | |
dc.contributor.author | Ding, Li | |
dc.contributor.author | Rovere, Matteo | |
dc.contributor.author | Wolfe, Michael S. | |
dc.contributor.author | Selkoe, Dennis J. | |
dc.date.accessioned | 2021-01-18T21:21:55Z | |
dc.date.available | 2021-01-18T21:21:55Z | |
dc.date.issued | 2019-01-09 | |
dc.identifier.citation | Lei 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: https://doi.org/10.1083/jcb.201806205 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/31180 | |
dc.description | This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. | en_US |
dc.description.abstract | Intramembrane 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.publisher | Rockefeller University Press | en_US |
dc.rights | © 2019 Liu et al. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | en_US |
dc.subject | Biochemistry | en_US |
dc.subject | Neuroscience | en_US |
dc.subject | Protein homeostasis | en_US |
dc.title | A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Wolfe, Michael S. | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1083/jcb.201806205 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-4604-4629 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-3260-4955 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0001-8846-9767 | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess | en_US |