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PMID: 17325205 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Rer1p competes with APH-1 for binding to nicastrin and regulates gamma-secretase complex assembly in the early secretory pathway.

The Journal of cell biology ·Vol. 176 ·No. 5 ·2007-02-26 ·Pages 629-40

Spasic D, Raemaekers T, Dillen K, Declerck I, Baert V, Serneels L, Füllekrug J, Annaert W

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.

MeSH Terms
Adaptor Proteins, Vesicular Transport Amino Acid Sequence Amyloid Precursor Protein Secretases/analysis,chemistry,metabolism Animals Binding, Competitive Down-Regulation Endopeptidases Endoplasmic Reticulum/metabolism Glycosylation Golgi Apparatus/metabolism HeLa Cells Humans Membrane Glycoproteins/analysis,chemistry,genetics,metabolism Membrane Proteins/metabolism Mice Molecular Sequence Data Peptide Hydrolases Protein Structure, Tertiary Sequence Alignment
Chemicals
Adaptor Proteins, Vesicular Transport Membrane Glycoproteins Membrane Proteins RER1 protein, human nicastrin protein APH1A protein, human Amyloid Precursor Protein Secretases Endopeptidases Peptide Hydrolases
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Spasic Dragana
Laboratory for Membrane Trafficking, Center for Human Genetics, Katholieke Universiteit Leuven/Vlaams Instituut voor Biotechnologie, Gasthuisberg, Leuven, B-3000 Leuven, Belgium.
Raemaekers Tim
Dillen Katleen
Declerck Ilse
Baert Veerle
Serneels Lutgarde
Füllekrug Joachim
Annaert Wim
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200609180
Published
2007-02-26
Pages
629-40
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2064021
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.200609180 PMC Full Text View journal details
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