The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha-, beta-, gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylation.
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The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha-, beta-, gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylation. / Eggert, Simone; Paliga, Krzysztof; Soba, Peter; Evin, Genevieve; Masters, Colin L; Weidemann, Andreas; Beyreuther, Konrad.
In: J BIOL CHEM, Vol. 279, No. 18, 18, 2004, p. 18146-18156.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha-, beta-, gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylation.
AU - Eggert, Simone
AU - Paliga, Krzysztof
AU - Soba, Peter
AU - Evin, Genevieve
AU - Masters, Colin L
AU - Weidemann, Andreas
AU - Beyreuther, Konrad
PY - 2004
Y1 - 2004
N2 - 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.
AB - 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.
KW - Humans
KW - Multigene Family
KW - Protein Processing, Post-Translational
KW - Binding Sites
KW - Cell Line
KW - Transfection
KW - Glycosylation
KW - Nerve Tissue Proteins/genetics/metabolism
KW - Amyloid Precursor Protein Secretases
KW - Amyloid beta-Protein Precursor/genetics/metabolism
KW - Aspartic Acid Endopeptidases
KW - Endopeptidases/metabolism
KW - Peptide Fragments/analysis
KW - Protease Inhibitors/pharmacology
KW - Humans
KW - Multigene Family
KW - Protein Processing, Post-Translational
KW - Binding Sites
KW - Cell Line
KW - Transfection
KW - Glycosylation
KW - Nerve Tissue Proteins/genetics/metabolism
KW - Amyloid Precursor Protein Secretases
KW - Amyloid beta-Protein Precursor/genetics/metabolism
KW - Aspartic Acid Endopeptidases
KW - Endopeptidases/metabolism
KW - Peptide Fragments/analysis
KW - Protease Inhibitors/pharmacology
M3 - SCORING: Journal article
VL - 279
SP - 18146
EP - 18156
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 18
M1 - 18
ER -
