Mutation of conserved aspartates affects maturation of both aspartate mutant and endogenous presenilin 1 and presenilin 2 complexes

Presenilin (PS1 and PS2) holoproteins are transiently incorporated into low molecular weight (MW) complexes. During subsequent incorporation into a hi gher MW complex, they undergo endoproteolysis to generate stable N- and C-t erminal fragments. Mutation of either of two conserved aspartate residues i n transmembrane domains inhibits both presenilin endoproteolysis and the pr oteolytic processing of beta-amyloid precursor protein and Notch. We show t hat although PS1/PS2 endoproteolysis is not required for inclusion into the higher MW N- and C-terminal fragment-containing complex, aspartate mutant holoprotein presenilins are not incorporated into the high MW complexes. As partate mutant presenilin holoproteins also preclude entry of endogenous wi ld type PS1/PS2 into the high MW complexes but do not affect the incorporat ion of wild type holoproteins into lower MW holoprotein complexes. These da ta suggest that the loss of function effects of the aspartate mutants resul t in altered PS complex maturation and argue that the functional presenilin moieties are contained in the high molecular weight complexes.