PEN-2 enhances γ-cleavage after presenilin heterodimer formation

被引:24
作者
Shiraishi, H
Sai, X
Wang, HQ
Maeda, Y
Kurono, Y
Nishimura, M
Yanagisawa, K
Komano, H
机构
[1] Natl Inst Longev Sci, Dept Dementia Res, Aichi 4748522, Japan
[2] Org Pharmaceut Safety & Res Japan, Chiyoda Ku, Tokyo, Japan
[3] Shiga Univ Med Sci, Mol Neurosci Res Ctr, Shiga, Japan
[4] Nagoya City Univ, Fac Pharmaceut Sci, Aichi, Japan
关键词
Alzheimer's disease; amyloid beta-protein; nicastrin; PEN-2; APH-1; presenilin;
D O I
10.1111/j.1471-4159.2004.02597.x
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
The presenilin (PS) complex, including PS, nicastrin, APH-1 and PEN-2, is essential for gamma-secretase activity, which is required for amyloid beta-protein (Abeta) generation. However, the precise individual roles of the three cofactors in the PS complex in Abeta generation remain to be clarified. Here, to distinguish the roles of PS cofactors in gamma-secretase activity from those in PS endoproteolysis, we investigated their roles in the gamma-secretase activity reconstituted by the coexpression of PS N- and C-terminal fragments (NTF and CTF) in PS-null cells. We demonstrate that the coexpression of PS1 NTF and CTF forms the heterodimer and restores Abeta generation in PS-null cells. The generation of Abeta was saturable at a certain expression level of PS1 NTF/CTF, while the overexpression of PEN-2 alone resulted in a further increase in Abeta generation. Although PEN-2 did not enhance PS1 NTF/CTF heterodimer formation, PEN-2 expression reduced the IC50 of a specific gamma-secretase inhibitor, a transition state analogue, for Abeta generation, suggesting that PEN-2 expression enhances the affinity or the accessibility of the substrate to the catalytic site. Thus, our results strongly suggest that PEN-2 is not only an essential component of the gamma-secretase complex but also an enhancer of gamma-cleavage after PS heterodimer formation.
引用
收藏
页码:1402 / 1413
页数:12
相关论文
共 62 条
[1]   LONG AMYLOID BETA-PROTEIN SECRETED FROM WILD-TYPE HUMAN NEUROBLASTOMA IMR-32 CELLS [J].
ASAMIODAKA, A ;
ISHIBASHI, Y ;
KIKUCHI, T ;
KITADA, C ;
SUZUKI, N .
BIOCHEMISTRY, 1995, 34 (32) :10272-10278
[2]   Pen-2 is sequestered in the endoplasmic reticulum and subjected to ubiquitylation and proteasome-mediated degradation in the absence of presenilin [J].
Bergman, A ;
Hansson, EM ;
Pursglove, SE ;
Farmery, MR ;
Lannfelt, L ;
Lendahl, U ;
Lundkvist, J ;
Näslund, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (16) :16744-16753
[3]   PROCESSING OF ALZHEIMER BETA-A4 AMYLOID PRECURSOR PROTEIN - MODULATION BY AGENTS THAT REGULATE PROTEIN-PHOSPHORYLATION [J].
BUXBAUM, JD ;
GANDY, SE ;
CICCHETTI, P ;
EHRLICH, ME ;
CZERNIK, AJ ;
FRACASSO, RP ;
RAMABHADRAN, TV ;
UNTERBECK, AJ ;
GREENGARD, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (15) :6003-6006
[4]   Presenilin modulates Pen-2 levels posttranslationally by protecting it from proteasomal degradation [J].
Crystal, AS ;
Morais, VA ;
Fortna, RR ;
Carlin, D ;
Pierson, TC ;
Wilson, CA ;
Lee, VMY ;
Doms, RW .
BIOCHEMISTRY, 2004, 43 (12) :3555-3563
[5]   A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain [J].
De Strooper, B ;
Annaert, W ;
Cupers, P ;
Saftig, P ;
Craessaerts, K ;
Mumm, JS ;
Schroeter, EH ;
Schrijvers, V ;
Wolfe, MS ;
Ray, WJ ;
Goate, A ;
Kopan, R .
NATURE, 1999, 398 (6727) :518-522
[6]   Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein [J].
De Strooper, B ;
Saftig, P ;
Craessaerts, K ;
Vanderstichele, H ;
Guhde, G ;
Annaert, W ;
Von Figura, K ;
Van Leuven, F .
NATURE, 1998, 391 (6665) :387-390
[7]   PRODUCTION OF INTRACELLULAR AMYLOID-CONTAINING FRAGMENTS IN HIPPOCAMPAL-NEURONS EXPRESSING HUMAN AMYLOID PRECURSOR PROTEIN AND PROTECTION AGAINST AMYLOIDOGENESIS BY SUBTLE AMINO-ACID SUBSTITUTIONS IN THE RODENT SEQUENCE [J].
DESTROOPER, B ;
SIMONS, M ;
MULTHAUP, G ;
VANLEUVEN, F ;
BEYREUTHER, K ;
DOTTI, CG .
EMBO JOURNAL, 1995, 14 (20) :4932-4938
[8]   Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain [J].
Dovey, HF ;
John, V ;
Anderson, JP ;
Chen, LZ ;
Andrieu, PD ;
Fang, LY ;
Freedman, SB ;
Folmer, B ;
Goldbach, E ;
Holsztynska, EJ ;
Hu, KL ;
Johnson-Wood, KL ;
Kennedy, SL ;
Kholedenko, D ;
Knops, JE ;
Latimer, LH ;
Lee, M ;
Liao, Z ;
Lieberburg, IM ;
Motter, RN ;
Mutter, LC ;
Nietz, J ;
Quinn, KP ;
Sacchi, KL ;
Seubert, PA ;
Shopp, GM ;
Thorsett, ED ;
Tung, JS ;
Wu, J ;
Yang, S ;
Yin, CT ;
Schenk, DB ;
May, PC ;
Altstiel, LD ;
Bender, MH ;
Boggs, LN ;
Britton, TC ;
Clemens, JC ;
Czilli, DL ;
Dieckman-McGinty, DK ;
Droste, JJ ;
Fuson, KS ;
Gitter, BD ;
Hyslop, PA ;
Johnstone, EM ;
Li, WY ;
Little, SP ;
Mabry, TE ;
Miller, FD ;
Ni, B .
JOURNAL OF NEUROCHEMISTRY, 2001, 76 (01) :173-181
[9]   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
[10]   Reconstitution of γ-secretase activity [J].
Edbauer, D ;
Winkler, E ;
Regula, JT ;
Pesold, B ;
Steiner, H ;
Haass, C .
NATURE CELL BIOLOGY, 2003, 5 (05) :486-488