The gamma-secretase complex processes substrate proteins within membranes and 
consists of four proteins: presenilin (PS), nicastrin, Aph-1 and Pen-2. PS 
harbours the enzymatic activity of the complex, and there are two mammalian PS 
homologues: PS1 and PS2. PS undergoes endoproteolysis, generating the N- and 
C-terminal fragments, NTF and CTF, which represent the active species of PS. To 
characterize the functional similarity between complexes of various PS 
composition, we analysed PS1, PS2, and chimeric PS composed of the NTF from PS1 
and CTF from PS2, or vice versa, in assembly and function of the gamma-secretase 
complex. Chimeric PSs, like PS1 and PS2, undergo normal endoproteolysis when 
introduced into cells devoid of endogenous PS. Furthermore, PS2 CTF can, at 
least partially, restore processing in a truncated PS1, which cannot undergo 
endoproteolysis. All PS forms enable maturation of nicastrin and cleave full 
length Notch receptors, indicating that both PS1 and PS2 are present at the cell 
surface. Finally, when co-introduced as separate molecules, NTF and CTF of 
different PS origin reconstitute gamma-secretase activity. In conclusion, these 
data show that endoproteolysis, NTF-CTF interactions, and the assembly and 
activity of gamma-secretase complexes are very conserved between PS1 and PS2.