The presenilin proteins are components of multiple membrane-bound complexes that have different biological activities.
Several lines of evidence have indicated that the presenilin proteins function within macromolecular complexes and are necessary for the regulated intramembranous proteolysis of certain type 1 transmembrane proteins, including the amyloid precursor protein, Notch, and p75. Data from multiple complementary experiments now suggest that there may be several distinct presenilin complexes. We show here that presenilin mutations and certain detergents affect the abundance and componentry of the presenilin complexes, and these structural effects correlate with their effects on gamma-secretase activity. Our data suggest that there are at least three complexes, including a approximately 150-kDa nicastrin-aph-1 complex (which is likely to be a precursor complex). There is a stable and abundant intermediate complex of approximately 440 kDa, which contains aph-1, pen-2, nicastrin, and PS1. However, it is the very low abundance, high mass (>/=670 kDa) heteromeric complexes that are associated with the highest gamma-secretase-specific activity.
Gu
Yongjun
Y
Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario M5S 3H2, Canada.
Sanjo
Nobuo
N
Chen
Fusheng
F
Hasegawa
Hiroshi
H
Petit
Agnes
A
Ruan
Xueying
X
Li
Wenping
W
Shier
Cortney
C
Kawarai
Toshitaka
T
Schmitt-Ulms
Gerold
G
Westaway
David
D
St George-Hyslop
Peter
P
Fraser
Paul E
PE
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D002478:Cells, Cultured; D003902:Detergents; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008970:Molecular Weight; D009154:Mutation; D009457:Neuroglia / Q000378:metabolism; D010447:Peptide Hydrolases; D053764:Presenilin-1; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D003902:Detergents; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C469349:PSENEN protein, human; D053764:Presenilin-1; D011994:Recombinant Proteins; C413604:nicastrin protein; C475154:APH1A protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse