Mutation of conserved aspartates affect maturation of presenilin 1 and presenilin 2 complexes
Acta Neurol Scand Suppl 176: 6-11
| Authors/Editors: |
Yu G Chen F Nishimura M Steiner H Tandon A Kawarai T Arawaka S Supala A Song YQ Rogaeva E Holmes E Zhang DM Milman P Fraser P Haass C St George-Hyslop P |
|---|---|
| Publication Date: | 2000 |
| Type of Publication: | Journal Article |
Presenilin (PS1 and PS2) holoproteins are transiently incorporated into low molecular weight (MW) complexes. During subsequent incorporation into a higher MW complex, they undergo endoproteolysis to generate stable N- and C-terminal 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-mutant holoprotein presenilins are not incorporated into the high molecular weight, NTF/CTF-containing complexes. Aspartate-mutant presenilin holoproteins also preclude entry of endogenous wild-type PS1/PS2 into the high molecular weight complexes, but do not affect the incorporation of wild-type holoproteins into lower molecular weight holoprotein complexes. These data suggest that the loss-of-function aspartate-mutants cause altered PS complex maturation, and argue that the functional presenilin moieties are contained in the high molecular weight presenilin NTF/CTF-containing complexes.
