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 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.
Centre for Research in Neurodegenerative Diseases, Department of Medical, Biophysics, University of Toronto, Ontario, Canada.
G
G
Yu
F
F
Chen
M
M
Nishimura
H
H
Steiner
A
A
Tandon
T
T
Kawarai
S
S
Arawaka
A
A
Supala
Y Q
YQ
Song
E
E
Rogaeva
E
E
Holmes
D M
DM
Zhang
P
P
Milman
P
P
Fraser
C
C
Haass
P
P
St George-Hyslop
D000544:Alzheimer Disease / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases; D018929:Cell Culture Techniques; D002462:Cell Membrane; D018076:DNA, Complementary / Q000235:genetics; D010450:Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D017354:Point Mutation; D053764:Presenilin-1; D053766:Presenilin-2; D011487:Protein Conformation
D016229:Amyloid beta-Peptides; D018076:DNA, Complementary; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D001224:Aspartic Acid; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse