Presenilin-1 and Presenilin-2 Exhibit Distinct yet Overlapping γ-Secretase Activities*
By M. Lai, E. Chen, Ming-Chih Crouthamel, J. DiMuzio-Mower, Min Xu, Qian Huang, Eric A. Price, R. Register, Xiao-ping Shi, D. Donoviel and 4 more. Journal of Biological Chemistry, 2003
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Presenilin-1 (PS1) and presenilin 2 (PS2) are proposed to be transmembrane aspartyl proteases that cleave amyloid precursor protein and Notch. PS1- and PS2-mediated activities were individually characterized using blastocyst-derived (BD) cells and membranes from PS1+/–-PS2–/– and PS1–/–PS2+/+ mice, respectively. The relative amounts of PS1 and PS2 in the various BD cells were determined from the intensities of the anti-PS1 and anti-PS2 immunoblot signals by comparison with standard curves using radiolabeled PS1 and PS2 standards produced by in vitro transcription and translation. Cellular membranes from wild type, PS1–/–PS2+/+, and PS1+/–-PS2–/– but not PS1–/–PS2–/– BD cells generated the Aβ40 and Aβ42 products from the C100FLAG substrate. PS1-associated γ-secretase displays considerably higher specific activity than PS2-associated γ-secretase. Moreover, the PS1+/–PS2–/– BD cells and corresponding membranes exhibited much higher γ-secretase activity as compared with other BD cells and membranes. The PS1-mediated γ-secretase activity correlated better with the amount of PS1 that is modifiable by a photoactivated active site-directed γ-secretase inhibitor rather than total PS1; hence, only a small portion (<14%) of the PS1 in wild-type membranes appears to be engaged in an active γ-secretase complex. This finding suggests that PS1 may serve other biological functions in addition to that associated with its γ-secretase activity. Furthermore, the PS1 γ-secretase complex and the PS2 γ-secretase complex activities can be discriminated on the basis of their susceptibility to inhibition by a potent γ-secretase inhibitor. The distinct yet overlapping enzymatic properties of the PS1 γ-secretase complex and the PS2 γ-secretase complex imply that these two putative aspartyl class proteases may contribute to different biological processes.
Subfields: Cell Biology, Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/df057dd66fdeed2fe4c9cf861306600bd585ab56
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- Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease (2005, methodology): “…PS dependent To confirm that fluorogenic substrate cleavage was PS1 specific, we assayed its activity in AVs that were isolated from JCB • VOLUME 171 • NUMBER 1 • 200594 PS1 PS2 knockout (PS KO) blastocysts (BD8; Lai et al., 2003) and BD8 blastocysts that were transfected with human PS1 (BD8/hPS1).”