Direct visualization of the gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein: association with Fe65 and translocation to the nucleus

被引：80

作者：

Kinoshita, A ^{[1
]}

Whelan, CM ^{[1
]}

Smith, CJ ^{[1
]}

Berezovska, O ^{[1
]}

Hyman, BT ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Alzheimer Unit,Alzheimer Dis Res Lab, Charlestown, MA 02129 USA

来源：

JOURNAL OF NEUROCHEMISTRY | 2002年 / 82卷 / 04期

关键词：

adapter protein; amyloid precursor protein; Fe65; FRET; gamma cleavage; intracellular domain;

D O I：

10.1046/j.1471-4159.2002.01016.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：

Amyloid-beta, the peptide that deposits as senile plaques in Alzheimer's disease, is derived from the amyloid precursor protein (APP) by a gamma secretase-mediated intramembranous cleavage. In addition to amyloid-beta, this cleavage produces a carboxyl-terminal intracellular fragment which has an unknown function. The carboxyl-terminal domain of APP interacts in the cytoplasm with an adapter protein, Fe65. We demonstrate by laser scanning confocal microscopy that a gamma secretase generated APP carboxyl-terminal domain, tagged with green fluorescent protein (GFP), translocates to the nucleus in a manner dependent upon stabilization by the adapter protein Fe65; APP which has been mutated to block interactions with Fe65 cannot be detected in the nucleus. The APP-CT domain continues to interact with Fe65 in the nucleus, as determined by both colocalization and fluorescence resonance energy transfer (FRET). Visualization of the APP-CT-Fe65 complex in the nucleus may serve as a readout for processes that modify gamma secretase release of APP-CT.

引用

页码：839 / 847

页数：9

共 35 条

[11]

ERICKSON AH, 1979, J BIOL CHEM, V254, P1771

[12] The regions of the Fe65 protein homologous to the phosphotyrosine interaction phosphotyrosine binding domain of Shc bind the intracellular domain of the Alzheimer's amyloid precursor protein [J].

Fiore, F ;

Zambrano, N ;

Minopoli, G ;

Donini, V ;

Duilio, A ;

Russo, T .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (52) :30853-30856

[13] The γ-secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus [J].

Gao, YH ;

Pimplikar, SW .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (26) :14979-14984

[14] Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein [J].

Guenette, SY ;

Chen, J ;

Jondro, PD ;

Tanzi, RE .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (20) :10832-10837

[15]

Howe S, 1999, STAND MAG, V1, P19

[16] The intracellular domain of the β-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a Notch-like manner [J].

Kimberly, WT ;

Zheng, JB ;

Guénette, SY ;

Selkoe, DJ .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (43) :40288-40292

[17] Demonstration by fluorescence resonance energy transfer of two sites of interaction between the low-density lipoprotein receptor-related protein and the amyloid precursor protein: Role of the intracellular adapter protein Fe65 [J].

Kinoshita, A ;

Whelan, CM ;

Smith, CJ ;

Mikhailenko, I ;

Rebeck, GW ;

Strickland, DK ;

Hyman, BT .

JOURNAL OF NEUROSCIENCE, 2001, 21 (21) :8354-8361

[18] Demonstration by fluorescence resonance energy transfer of a close association between activated MAP kinase and neurofibrillary tangles: Implications for MAP kinase activation in Alzheimer disease [J].

Knowles, RB ;

Chin, J ;

Ruff, CT ;

Hyman, BT .

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 1999, 58 (10) :1090-1098

[19]

Matsuda S, 2001, J NEUROSCI, V21, P6597

[20] Membrane association and protein conformation of α-synuclein in intact neurons -: Effect of Parkinson's disease-linked mutations [J].

McLean, PJ ;

Kawamata, H ;

Ribich, S ;

Hyman, BT .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (12) :8812-8816

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