Reconstitution of γ-secretase activity

被引：749

作者：

Edbauer, D

Winkler, E

Regula, JT

Pesold, B

Steiner, H ^{[1
]}

Haass, C

机构：

[1] Univ Munich, Adolf Butenandt Inst, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany

[2] Univ Munich, Adolf Butenandt Inst, Protein Anal Unit, D-80336 Munich, Germany

来源：

NATURE CELL BIOLOGY | 2003年 / 5卷 / 05期

关键词：

D O I：

10.1038/ncb960

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

gamma-Secretase is a membrane protein complex with an unusual aspartyl protease activity that catalyses the regulated intramembranous cleavage of the beta-amyloid precursor protein (APP) to release the Alzheimer's disease (AD)-associated amyloid beta-peptide (Abeta) and the APP intracellular domain (AICD)(1). Here we show the reconstitution of gamma-secretase activity in the yeast Saccharomyces cerevisiae, which lacks endogenous gamma-secretase activity. Reconstituted gamma-secretase activity depends on the presence of four complex components including presenilin (PS)(1), nicastrin (Nct)(2), APH-1 (refs 3-6) and PEN-2 (refs 4, 7), is associated with endoproteolysis of PS8, and produces Abeta and AICD in vitro. Thus, the biological activity of gamma-secretase is reconstituted by the co-expression of human PS, Nct, APH-1 and PEN-2 in yeast.

引用

页码：486 / 488

页数：3

共 15 条

[1] Presenilin and nicastrin regulate each other and determine amyloid β-peptide production via complex formation [J].

Edbauer, D ;

Winkler, E ;

Haass, C ;

Steiner, H .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (13) :8666-8671

[2] Activity-dependent isolation of the presenilin-γ-secretase complex reveals nicastrin and a γ substrate [J].

Esler, WP ;

Kimberly, WT ;

Ostaszewski, BL ;

Ye, WJ ;

Diehl, TS ;

Selkoe, DJ ;

Wolfe, MS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (05) :2720-2725

[3] aph-1 and pen-2 are required for notch pathway signaling, γ-secretase cleavage of βAPP, and presenilin protein accumulation [J].

Francis, R ;

McGrath, G ;

Zhang, JH ;

Ruddy, DA ;

Sym, M ;

Apfeld, J ;

Nicoll, M ;

Maxwell, M ;

Hai, B ;

Ellis, MC ;

Parks, AL ;

Xu, W ;

Li, JH ;

Gurney, M ;

Myers, RL ;

Himes, CS ;

Hiebsch, R ;

Ruble, C ;

Nye, JS ;

Curtis, D .

DEVELOPMENTAL CELL, 2002, 3 (01) :85-97

[4] APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos [J].

Goutte, C ;

Tsunozaki, M ;

Hale, VA ;

Priess, JR .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (02) :775-779

[5] APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin-nicastrin complexes [J].

Gu, YJ ;

Chen, FS ;

Sanjo, N ;

Kawarai, T ;

Hasegawa, H ;

Duthie, M ;

Li, WP ;

Ruan, XY ;

Luthra, A ;

Mount, HTJ ;

Tandon, A ;

Fraser, PE ;

St George-Hyslop, P .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (09) :7374-7380

[6] Alzheimer disease γ-secretase:: a complex story of GxGD-type presenilin proteases [J].

Haass, C ;

Steiner, H .

TRENDS IN CELL BIOLOGY, 2002, 12 (12) :556-562

[7] Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-β precursor protein and Notch [J].

Lee, SF ;

Shah, S ;

Li, HQ ;

Yu, C ;

Han, WP ;

Yu, G .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (47) :45013-45019

[8] Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1 [J].

Li, YM ;

Xu, M ;

Lai, MT ;

Huang, Q ;

Castro, JL ;

DiMuzio-Mower, J ;

Harrison, T ;

Lellis, C ;

Nadin, JL ;

Neduvelil, JG ;

Sardana, MK ;

Shearman, MS ;

Smith, AL ;

Shi, XP ;

Yin, KC ;

Shafer, JA ;

Gardell, SJ .

NATURE, 2000, 405 (6787) :689-694

[9] Presenilin dependent γ-secretase processing of β-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch [J].

Sastre, M ;

Steiner, H ;

Fuchs, K ;

Capell, A ;

Multhaup, G ;

Condron, MM ;

Teplow, DB ;

Haass, C .

EMBO REPORTS, 2001, 2 (09) :835-841

[10] PEN-2 is an integral component of the γ-secretase complex required for coordinated expression of presenilin and nicastrin [J].

Steiner, H ;

Winkler, E ;

Edbauer, D ;

Prokop, S ;

Basset, G ;

Yamasaki, A ;

Kostka, M ;

Haass, C .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (42) :39062-39065

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