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 higher MW complex, they undergo endoproteolysis to generate stable N- and C-terminal fragments. Mutation of either of two conserved aspartate residues in transmembrane domains inhibits both presenilin-endoproteolysis and the proteolytic processing of beta-amyloid precursor protein and Notch. We show that 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. Aspartate mutant presenilin holoproteins also preclude entry of endogenous wild type PS1/PS2 into the high MW complexes but do not affect the incorporation of wild type holoproteins into lower MW holoprotein complexes. These data suggest that the loss of function effects of the aspartate mutants result in altered PS complex maturation and argue that the functional presenilin moieties are contained in the high molecular weight complexes.
Yu
G
G
Centre for Research in Neurodegenerative Diseases, Departments of Medical Biophysics and Medicine, University of Toronto, Ontario, Canada.
Chen
F
F
Nishimura
M
M
Steiner
H
H
Tandon
A
A
Kawarai
T
T
Arawaka
S
S
Supala
A
A
Song
Y Q
YQ
Rogaeva
E
E
Holmes
E
E
Zhang
D M
DM
Milman
P
P
Fraser
P E
PE
Haass
C
C
George-Hyslop
P S
PS
D001224:Aspartic Acid / Q000235:genetics*; D002460:Cell Line; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D016296:Mutagenesis; D053764:Presenilin-1; D053766:Presenilin-2; D011499:Protein Processing, Post-Translational
D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D001224:Aspartic Acid