A cellular complex of BACE1 and {gamma}-secretase sequentially generates A{beta} from its full-length precursor

We describe a hitherto unrecognized multiprotease complex containing active β- 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 β- and -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 -secretase modulators. Alzheimer’s-causing mutations in presenilin altered the Aβ42/40 peptide ratio generated by the HMW β/-secretase complex indistinguishably from that observed in whole cells. Thus, Aβ is generated from holo-APP by a BACE1–-secretase complex that provides sequential, efficient RIP processing of full-length substrates to final products.

Source: Journal of Cell Biology - February 4, 2019 Category: Cytology Authors: Liu, L., Ding, L., Rovere, M., Wolfe, M. S., Selkoe, D. J. Tags: Protein Homeostasis, Biochemistry, Neuroscience Articles Source Type: research