that "snip" pieces off a longer protein
that is embedded in the cell membrane
. Among other roles in the cell
, secretases act on the amyloid precursor protein
(APP) to cleave the protein into three fragments. Sequential cleavage by β-secretase
(BACE) and γ-secretase
produces the amyloid-β
peptide fragment that aggregates into clumps called "plaques" in the brains
of Alzheimer's disease
patients. If α-secretase
acts on APP first instead of BACE, no amyloid-β is formed because α-secretase recognizes a target protein sequence
closer to the cell surface than BACE. The non-pathogenic middle fragment formed by an α/γ cleavage sequence is called P3.
of the three secretases varies widely.
Besides their involvement in the pathogenesis of Alzheimer's, these proteins also have other functional roles in the cell.
γ-secretase plays a critical role in developmental signalling by the transmembrane receptor Notch, freeing the cytoplasmic tail of Notch to travel to the cell nucleus to act as a transcription factor.
Although BACE cleaves the extracellular domains of several transmembrane proteins, its physiological function remains unknown.