Figure 1.

Proteolytic processing of the BACE1 substrates APP and NRG1. (A) Regulated intramembrane proteolysis of APP occurs by two alternative pathways. In the amyloidogenic pathway, ectodomain shedding by BACE1 releases the soluble APP ectodomain and generates the N-terminus of the Aβ peptide. The membrane-bound CTF (C99) is then further processed by γ-secretase, which releases the Aβ peptide into the extracellular space and the APP intracellular domain (AICD) into the cytosol where it is rapidly degraded. In the alternative, anti-amyloidogenic pathway, ectodomain shedding is mediated by ADAM10. Cleavage occurs in the middle of the Aβ domain and yields the soluble APP ectodomain and a CTF (C83), which is further processed by γ-secretase to generate the secreted p3 peptide (not shown). (B) Ectodomain shedding of type III NRG1 by BACE1 or ADAM10 occurs C-terminally of the EGF-like domain and generates a large NTF as well as a shorter CTF. Cleavage by BACE1 leads to a slightly larger NTF, that exerts signaling function. Cleavage within the EGF-like domain by ADAM17 appears to render the resulting NTF inactive (not shown). The remaining CTF is further processed by γ-secretase in order to yield the NRG1-ICD.