Title: Rer1p competes with APH-1 for binding to nicastrin and regulates gamma-secretase complex assembly in the early secretory pathway
Authors: Spasic, Dragana ×
Raemaekers, Tim
Dillen, Katleen
Declerck, Ilse
Baert, Veerle
Serneels, Lutgarde
Füllekrug, Joachim
Annaert, Wim #
Issue Date: Feb-2007
Series Title: Journal of Cell Biology vol:176 issue:5 pages:629-40
Abstract: The gamma-secretase complex, consisting of presenilin, nicastrin, presenilin enhancer-2 (PEN-2), and anterior pharynx defective-1 (APH-1) cleaves type I integral membrane proteins like amyloid precursor protein and Notch in a process of regulated intramembrane proteolysis. The regulatory mechanisms governing the multistep assembly of this "proteasome of the membrane" are unknown. We characterize a new interaction partner of nicastrin, the retrieval receptor Rer1p. Rer1p binds preferentially immature nicastrin via polar residues within its transmembrane domain that are also critical for interaction with APH-1. Absence of APH-1 substantially increased binding of nicastrin to Rer1p, demonstrating the competitive nature of these interactions. Moreover, Rer1p expression levels control the formation of gamma-secretase subcomplexes and, concomitantly, total cellular gamma-secretase activity. We identify Rer1p as a novel limiting factor that negatively regulates gamma-secretase complex assembly by competing with APH-1 during active recycling between the endoplasmic reticulum (ER) and Golgi. We conclude that total cellular gamma-secretase activity is restrained by a secondary ER control system that provides a potential therapeutic value.
ISSN: 0021-9525
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
Biomedical Sciences Group Management - miscellaneous
× corresponding author
# (joint) last author

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