共 48 条
Detergent-dependent dissociation of active γ-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex
被引:112
作者:

Fraering, PC
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机构: Harvard Univ, Sch Med, Inst Med 730, Ctr Neurol Dis, Boston, MA 02115 USA

LaVoie, MJ
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h-index: 0
机构: Harvard Univ, Sch Med, Inst Med 730, Ctr Neurol Dis, Boston, MA 02115 USA

Ye, WJ
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h-index: 0
机构: Harvard Univ, Sch Med, Inst Med 730, Ctr Neurol Dis, Boston, MA 02115 USA

Ostaszewski, BL
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h-index: 0
机构: Harvard Univ, Sch Med, Inst Med 730, Ctr Neurol Dis, Boston, MA 02115 USA

Kimberly, WT
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机构: Harvard Univ, Sch Med, Inst Med 730, Ctr Neurol Dis, Boston, MA 02115 USA

Selkoe, DJ
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h-index: 0
机构: Harvard Univ, Sch Med, Inst Med 730, Ctr Neurol Dis, Boston, MA 02115 USA

Wolfe, MS
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h-index: 0
机构: Harvard Univ, Sch Med, Inst Med 730, Ctr Neurol Dis, Boston, MA 02115 USA
机构:
[1] Harvard Univ, Sch Med, Inst Med 730, Ctr Neurol Dis, Boston, MA 02115 USA
[2] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA
关键词:
D O I:
10.1021/bi035748j
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:
gamma-Secretase is a member of a new class of proteases with an intramembrane catalytic site and cleaves numerous type I membrane proteins, including the amyloid beta-protein precursor (APP) and the Notch receptor. Biochemical and genetic studies have identified four membrane proteins as components of gamma-secretase: a heterodimeric form of presenilin (PS), composed of its N- and C-terminal fragments (PS-NTF and PS-CTF, respectively), a highly glycosylated, mature form of nicastrin (NCT), Aph-1, and Pen-2. However, it is unclear how these components interact physically with each other and assemble into functional complexes. We and others recently found that Aph-1 interacts with a less glycosylated, immature form of nicastrin as an intermediate toward full assembly of gamma-secretase. Here we show that (1) the detergent dodecyl beta-D-maltoside (DDM) mediates the dissociation and inactivation of active gamma-secretase in a concentration-dependent manner, (2) DDM-dependent dissociation of the active gamma-secretase complex generates two major inactive complexes (Pen-2-PS1-NTF and mNCT-Aph-1) and two minor inactive complexes (mNCT-Aph1-PS1-CTF and PS1-NTF-PS1-CTF), and (3) Pen-2 can also associate with the PS holoprotein in complexes devoid of NCT and Aph-1. Taken together, our results demonstrate that Pen-2 interacts with PS-NTF within active gamma-secretase and offer a model for how the components of active gamma-secretase interact physically with each other.
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页码:323 / 333
页数:11
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