共 62 条
PEN-2 enhances γ-cleavage after presenilin heterodimer formation
被引:24
作者:

Shiraishi, H
论文数: 0 引用数: 0
h-index: 0
机构: Natl Inst Longev Sci, Dept Dementia Res, Aichi 4748522, Japan

Sai, X
论文数: 0 引用数: 0
h-index: 0
机构: Natl Inst Longev Sci, Dept Dementia Res, Aichi 4748522, Japan

Wang, HQ
论文数: 0 引用数: 0
h-index: 0
机构: Natl Inst Longev Sci, Dept Dementia Res, Aichi 4748522, Japan

Maeda, Y
论文数: 0 引用数: 0
h-index: 0
机构: Natl Inst Longev Sci, Dept Dementia Res, Aichi 4748522, Japan

Kurono, Y
论文数: 0 引用数: 0
h-index: 0
机构: Natl Inst Longev Sci, Dept Dementia Res, Aichi 4748522, Japan

Nishimura, M
论文数: 0 引用数: 0
h-index: 0
机构: Natl Inst Longev Sci, Dept Dementia Res, Aichi 4748522, Japan

Yanagisawa, K
论文数: 0 引用数: 0
h-index: 0
机构: Natl Inst Longev Sci, Dept Dementia Res, Aichi 4748522, Japan

Komano, H
论文数: 0 引用数: 0
h-index: 0
机构: Natl Inst Longev Sci, Dept Dementia Res, Aichi 4748522, Japan
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.
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页码:1402 / 1413
页数:12
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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

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h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

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h-index: 0
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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

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h-index: 0
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h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

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h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

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h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Gitter, BD
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h-index: 0
机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Hyslop, PA
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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Johnstone, EM
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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Li, WY
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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Little, SP
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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Mabry, TE
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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Miller, FD
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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA

Ni, B
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机构: Elan Pharmaceut Inc, S San Francisco, CA 94080 USA
[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
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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,
2002, 99 (13)
:8666-8671

Edbauer, D
论文数: 0 引用数: 0
h-index: 0
机构:
Univ Munich, Adolf Butenandt, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany Univ Munich, Adolf Butenandt, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany

Winkler, E
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h-index: 0
机构:
Univ Munich, Adolf Butenandt, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany Univ Munich, Adolf Butenandt, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany

Haass, C
论文数: 0 引用数: 0
h-index: 0
机构:
Univ Munich, Adolf Butenandt, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany Univ Munich, Adolf Butenandt, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany

Steiner, H
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h-index: 0
机构:
Univ Munich, Adolf Butenandt, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany Univ Munich, Adolf Butenandt, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany
[10]
Reconstitution of γ-secretase activity
[J].
Edbauer, D
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Winkler, E
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Regula, JT
;
Pesold, B
;
Steiner, H
;
Haass, C
.
NATURE CELL BIOLOGY,
2003, 5 (05)
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Edbauer, D
论文数: 0 引用数: 0
h-index: 0
机构: Univ Munich, Adolf Butenandt Inst, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany

Winkler, E
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机构: Univ Munich, Adolf Butenandt Inst, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany

Regula, JT
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机构: Univ Munich, Adolf Butenandt Inst, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany

Pesold, B
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h-index: 0
机构: Univ Munich, Adolf Butenandt Inst, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany

Steiner, H
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h-index: 0
机构:
Univ Munich, Adolf Butenandt Inst, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany Univ Munich, Adolf Butenandt Inst, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany

Haass, C
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机构: Univ Munich, Adolf Butenandt Inst, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany