The presenilin proteins are components of multiple membrane-bound complexes that have different biological activities

被引:66
作者
Gu, YJ
Sanjo, N
Chen, FS
Hasegawa, H
Petit, A
Ruan, XY
Li, WP
Shier, C
Kawarai, T
Schmitt-Ulms, G
Westaway, D
St George-Hyslop, P
Fraser, PE
机构
[1] Univ Toronto, Dept Med, Ctr Res Neurodegenerat Dis, Toronto, ON M5S 3H2, Canada
[2] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 3H2, Canada
[3] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 3H2, Canada
[4] Toronto Western Hosp, Dept Med, Div Neurol, Toronto, ON M5S 3H2, Canada
关键词
D O I
10.1074/jbc.M401548200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 similar to150-kDa nicastrin-aph-1 complex ( which is likely to be a precursor complex). There is a stable and abundant intermediate complex of similar to 440 kDa, which contains aph-1, pen-2, nicastrin, and PS1. However, it is the very low abundance, high mass (greater than or equal to 670 kDa) heteromeric complexes that are associated with the highest gamma-secretase-specific activity.
引用
收藏
页码:31329 / 31336
页数:8
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