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A cellular complex of BACE1 and ?-secretase sequentially generates A? from its full-length precursor.

ABSTRACT: Intramembrane proteolysis of transmembrane substrates by the presenilin-?-secretase complex is preceded and regulated by shedding of the substrate's ectodomain by ?- or ?-secretase. We asked whether ?- and ?-secretases interact to mediate efficient sequential processing of APP, generating the amyloid ? (A?) peptides that initiate Alzheimer's disease. We describe a hitherto unrecognized multiprotease complex containing active ?- and ?-secretases. BACE1 coimmunoprecipitated and cofractionated with ?-secretase in cultured cells and in mouse and human brain. An endogenous high molecular weight (HMW) complex (?5 MD) containing ?- and ?-secretases and holo-APP was catalytically active in vitro and generated a full array of A? peptides, with physiological A?42/40 ratios. The isolated complex responded properly to ?-secretase modulators. Alzheimer's-causing mutations in presenilin altered the A?42/40 peptide ratio generated by the HMW ?/?-secretase complex indistinguishably from that observed in whole cells. Thus, A? is generated from holo-APP by a BACE1-?-secretase complex that provides sequential, efficient RIP processing of full-length substrates to final products.

SUBMITTER: Liu L 

PROVIDER: S-EPMC6363461 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor.

Liu Lei L   Ding Li L   Rovere Matteo M   Wolfe Michael S MS   Selkoe Dennis J DJ  

The Journal of cell biology 20190109 2

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  ...[more]

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