A Novel ε-Cleavage within the Transmembrane Domain of the Alzheimer Amyloid 
Precursor Protein Demonstrates Homology with Notch Processing

Weidemann, Andreas; Eggert, Simone; Reinhard, Friedrich B. M.; Vogel, Markus; Paliga, Krzysztof; Baier, Gottfried; Masters, Colin L.; Beyreuther, Konrad; Evin, Geneviève

doi:10.1021/bi015794o

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A Novel ε-Cleavage within the Transmembrane Domain of the Alzheimer Amyloid Precursor Protein Demonstrates Homology with Notch Processing

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https://doi.org/10.1021/bi015794o
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引用

Weidemann, A., Eggert, S., Reinhard, F. B. M., Vogel, M., Paliga, K., Baier, G., Masters, C. L., Beyreuther, K., & Evin, G. (2002). A Novel ε-Cleavage within the Transmembrane Domain of the Alzheimer Amyloid Precursor Protein Demonstrates Homology with Notch Processing. Biochemistry, 41(8), 2825-2835. doi:10.1021/bi015794o.

引用: https://hdl.handle.net/21.11116/0000-000E-3E2F-A

要旨

Proteolytic processing of the transmembrane domain of the amyloid precursor protein (APP) is a key component of Alzheimer's disease pathogenesis. Using C-terminally tagged APP derivatives, we have identified by amino-terminal sequencing a novel cleavage site of APP, at Leu-49, distal to the γ-secretase site. This was termed ε-cleavage. Brefeldin A treatment and pulse−chase experiments indicate that this cleavage occurs late in the secretory pathway. The level of ε-cleavage is decreased by expression of presenilin-1 mutants known to impair Aβ formation, and it is sensitive to the γ-secretase inhibitors MDL28170 and L-685,458. Remarkably, it shares similarities with site 3 cleavage of Notch-1: membrane topology, cleavage before a valine, dependence on presenilins, and inhibition profile.