Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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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.

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