Mutation of conserved aspartates affect maturation of 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 (NTF/CTF). Mutation of either of two conserved aspartate residues in transmembrane domains inhibits both presenilin-endoproteolysis and the proteolytic processing of APP and Notch. We show that aspartate-mut ant holoprotein presenilins are not incorporated into the high molecular we ight, NTF/CTF-containing complexes. Aspartate-mutant presenilin holoprotein s also preclude entry of endogenous wild-type PS1/PS2 into the high molecul ar weight complexes, but do not affect the incorporation of wild-type holop roteins into lower molecular weight holoprotein complexes. These data sugge st that the loss-of-function aspartate-mutants cause altered PS complex mat uration, and argue that the functional presenilin moieties are contained in the high molecular weight presenilin NTF/CTF-containing complexes.