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Presenilin endoproteolysis mediated by an aspartyl protease activity pharmacologically distinct from γ‐secretase
Author(s) -
Campbell William A.,
Reed Megan L. O.,
Strahle Jennifer,
Wolfe Michael S.,
Xia Weiming
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01799.x
Subject(s) - presenilin , protease , biochemistry , transition state analog , amyloid precursor protein secretase , chemistry , pepstatin , amyloid precursor protein , enzyme , cleavage (geology) , active site , biology , alzheimer's disease , medicine , disease , pathology , paleontology , fracture (geology)
Presenilin (PS)‐dependent γ‐secretase cleavage is the final proteolytic step in generating amyloid β protein (Aβ), a key peptide involved in the pathogenesis of Alzheimer's disease. PS undergoes endoproteolysis by an unidentified ‘presenilinase’ to generate the functional N‐terminal and C‐terminal fragment heterodimers (NTF/CTF) that may harbor the γ‐secretase active site. To better understand the relationship between presenilinase and γ‐secretase, we characterized the biochemical properties of presenilinase and compared them with those of γ‐secretase. Similar to γ‐secretase, presenilinase was most active at acidic pH 6.3. Aspartyl protease inhibitor pepstatin A blocked presenilinase activity with an IC 50 of ∼ 1 µ m . Difluoroketone aspartyl protease transition state analogue MW167 was relatively selective for presenilinase (IC 50 < 1 µ m ) over γ‐secretase (IC 50 −16 µ m ). Importantly, removing the transition state mimicking moiety simultaneously abolished both presenilinase and γ‐secretase inhibition, suggesting that presenilinase, like γ‐secretase, is an aspartyl protease. Interestingly, several of the most potent γ‐secretase inhibitors (IC 50 = 0.3 or 20 n m ) failed to block presenilinase activity. Although de novo generation of PS1 fragments coincided with production of Aβ in vitro , blocking presenilinase activity without reducing pre‐existing fragment levels permitted normal de novo generation of Aβ and amyloid intracellular domain. Therefore, presenilinase has characteristics of an aspartyl protease, but this activity is distinct from γ‐secretase.