The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves α-, β-, γ-, and ε-like cleavages -: Modulation of APLP-1 processing by N-glycosylation

被引:183
作者
Eggert, S
Paliga, K
Soba, P
Evin, G
Masters, CL
Weidemann, A
Beyreuther, K
机构
[1] Zentrum Mol Biol Heidelberg, D-69120 Heidelberg, Germany
[2] Univ Kiel, Fac Med, Inst Biochem, D-24098 Kiel, Germany
[3] Univ Melbourne, Mental Hlth Res Inst, Dept Pathol, Parkville, Vic 3010, Australia
关键词
D O I
10.1074/jbc.M311601200
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 precursor protein (APP) processing is of major interest in Alzheimer's disease research, since sequential cleavages by beta- and gamma-secretase lead to the formation of the 4-kDa amyloid Abeta protein peptide that accumulates in Alzheimer's disease brain. The processing of APP involves proteolytic conversion by different secretases leading to alpha-, beta-, gamma-, delta-, and epsilon-cleavages. Since modulation of these cleavages represents a rational therapeutic approach to control amyloid formation, its interference with the processing of the members of the APP gene family is of considerable importance. By using C-terminally tagged constructs of APLP-1 and APLP-2 and the untagged proteins, we have characterized their proteolytic C-terminal fragments produced in stably transfected SH-SY5Y cells. Pharmacological manipulation with specific protease inhibitors revealed that both homologues are processed by alpha- and gamma-secretase-like cleavages, and that their intracellular domains can be released by cleavage at epsilon-sites. APLP-2 processing appears to be the most elaborate and to involve alternative cleavage sites. We show that APLP-1 is the only member of the APP gene family for which processing can be influenced by N-glycosylation. Additionally, we were able to detect p3-like fragments of APLP-1 and p3-like and Abeta-like fragments of APLP-2 in the media of stably transfected SH-SY5Y cells.
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页码:18146 / 18156
页数:11
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共 90 条
[1]   Diverse cell surface protein ectodomains are shed by a system sensitive to metalloprotease inhibitors [J].
Arribas, J ;
Coodly, L ;
Vollmer, P ;
Kishimoto, TK ;
RoseJohn, S ;
Massague, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (19) :11376-11382
[2]   Regulated intramembrane proteolysis: A control mechanism conserved from bacteria to humans [J].
Brown, MS ;
Ye, J ;
Rawson, RB ;
Goldstein, JL .
CELL, 2000, 100 (04) :391-398
[3]   Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor [J].
Buxbaum, JD ;
Liu, KN ;
Luo, YX ;
Slack, JL ;
Stocking, KL ;
Peschon, JJ ;
Johnson, RS ;
Castner, BJ ;
Cerretti, DP ;
Black, RA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (43) :27765-27767
[4]   A transcriptively active complex of APP with Fe65 and histone acetyltransferase Tip60 [J].
Cao, XW ;
Südhof, TC .
SCIENCE, 2001, 293 (5527) :115-120
[5]   Evidence that the 42- and 40-amino acid forms of amyloid beta protein are generated from the beta-amyloid precursor protein by different protease activities [J].
Citron, M ;
Diehl, TS ;
Gordon, G ;
Biere, AL ;
Seubert, P ;
Selkoe, DJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (23) :13170-13175
[6]   GENERATION OF AMYLOID-BETA PROTEIN FROM ITS PRECURSOR IS SEQUENCE-SPECIFIC [J].
CITRON, M ;
TEPLOW, DB ;
SELKOE, DJ .
NEURON, 1995, 14 (03) :661-670
[7]   What the evolution of the amyloid protein precursor supergene family tells us about its function [J].
Coulson, EJ ;
Paliga, K ;
Beyreuther, K ;
Masters, CL .
NEUROCHEMISTRY INTERNATIONAL, 2000, 36 (03) :175-184
[8]   Structure and functions of the 20S and 26S proteasomes [J].
Coux, O ;
Tanaka, K ;
Goldberg, AL .
ANNUAL REVIEW OF BIOCHEMISTRY, 1996, 65 :801-847
[9]   A METALLOPROTEASE INHIBITOR BLOCKS SHEDDING OF THE 80-KD TNF RECEPTOR AND TNF PROCESSING IN T-LYMPHOCYTES [J].
CROWE, PD ;
WALTER, BN ;
MOHLER, KM ;
OTTENEVANS, C ;
BLACK, RA ;
WARE, CF .
JOURNAL OF EXPERIMENTAL MEDICINE, 1995, 181 (03) :1205-1210
[10]   Aph-1, Pen-2, and nicastrin with presenilin generate an active γ-secretase complex [J].
De Strooper, B .
NEURON, 2003, 38 (01) :9-12