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Lai, M.T. et al.

Lai, Chen, Crouthamel, DiMuzio-Mower, Xu, Huang, Price, Register, Shi, Donoviel, Bernstein, Hazuda, Gardell, Li,

Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities.

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 Abeta40 and Abeta42 products from the C100FLAG substrate. PS1- associated gamma-secretase displays considerably higher specific activity than PS2-associated gamma-secretase. Moreover, the PS1+/-PS2-/- BD cells and corresponding membranes exhibited much higher gamma-secretase activity as compared with other BD cells and membranes. The PS1-mediated gamma-secretase activity correlated better with the amount of PS1 that is modifiable by a photoactivated active site-directed gamma-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 gamma-secretase complex. This finding suggests that PS1 may serve other biological functions in addition to that associated with its gamma-secretase activity. Furthermore, the PS1 gamma-secretase complex and the PS2 gamma-secretase complex activities can be discriminated on the basis of their susceptibility to inhibition by a potent gamma-secretase inhibitor. The distinct yet overlapping enzymatic properties of the PS1 gamma-secretase complex and the PS2 gamma-secretase complex imply that these two putative aspartyl class proteases may contribute to different biological processes.[1]

References

Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities. Lai, M.T., Chen, E., Crouthamel, M.C., DiMuzio-Mower, J., Xu, M., Huang, Q., Price, E., Register, R.B., Shi, X.P., Donoviel, D.B., Bernstein, A., Hazuda, D., Gardell, S.J., Li, Y.M. J. Biol. Chem. (2003) [Pubmed]

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