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A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor
Liu, Lei Ding, Li Rovere, Matteo Wolfe, Michael S. Selkoe, Dennis J.
Liu, Lei
Ding, Li
Rovere, Matteo
Wolfe, Michael S.
Selkoe, Dennis J.
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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.
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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Date
2019-01-09
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Rockefeller University Press
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Keywords
Biochemistry, Neuroscience, Protein homeostasis
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