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Different cofactor activities in γ-secretase assembly: evidence for a nicastrin–Aph-1 subcomplex

The γ-secretase complex is required for intramembrane cleavage of several integral membrane proteins, including the Notch receptor, where it generates an active signaling fragment. Four putative γ-secretase components have been identified—presenilin (Psn), nicastrin (Nct), Aph-1, and Pen-2. Here, we...

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Detalles Bibliográficos
Autores principales: Hu, Yue, Fortini, Mark E.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2003
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2199374/
https://www.ncbi.nlm.nih.gov/pubmed/12771124
http://dx.doi.org/10.1083/jcb.200304014
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author Hu, Yue
Fortini, Mark E.
author_facet Hu, Yue
Fortini, Mark E.
author_sort Hu, Yue
collection PubMed
description The γ-secretase complex is required for intramembrane cleavage of several integral membrane proteins, including the Notch receptor, where it generates an active signaling fragment. Four putative γ-secretase components have been identified—presenilin (Psn), nicastrin (Nct), Aph-1, and Pen-2. Here, we use a stepwise coexpression approach to investigate the role of each new component in γ-secretase assembly and activation. Coexpression of all four proteins leads to high level accumulation of mature Psn and increased proteolysis of Notch. Aph-1 and Nct may form a subcomplex that stabilizes the Psn holoprotein at an early step in γ-secretase assembly. Subcomplex levels of Aph-1 are down-regulated by stepwise addition of Psn, suggesting that Aph-1 might not enter the mature complex. In contrast, Pen-2 accumulates proportionally with Psn, and is associated with Psn endoproteolysis during γ-secretase assembly. These results demonstrate that Aph-1 and Pen-2 are essential cofactors for Psn, but that they play different roles in γ-secretase assembly and activation.
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spelling pubmed-21993742008-05-01 Different cofactor activities in γ-secretase assembly: evidence for a nicastrin–Aph-1 subcomplex Hu, Yue Fortini, Mark E. J Cell Biol Report The γ-secretase complex is required for intramembrane cleavage of several integral membrane proteins, including the Notch receptor, where it generates an active signaling fragment. Four putative γ-secretase components have been identified—presenilin (Psn), nicastrin (Nct), Aph-1, and Pen-2. Here, we use a stepwise coexpression approach to investigate the role of each new component in γ-secretase assembly and activation. Coexpression of all four proteins leads to high level accumulation of mature Psn and increased proteolysis of Notch. Aph-1 and Nct may form a subcomplex that stabilizes the Psn holoprotein at an early step in γ-secretase assembly. Subcomplex levels of Aph-1 are down-regulated by stepwise addition of Psn, suggesting that Aph-1 might not enter the mature complex. In contrast, Pen-2 accumulates proportionally with Psn, and is associated with Psn endoproteolysis during γ-secretase assembly. These results demonstrate that Aph-1 and Pen-2 are essential cofactors for Psn, but that they play different roles in γ-secretase assembly and activation. The Rockefeller University Press 2003-05-26 /pmc/articles/PMC2199374/ /pubmed/12771124 http://dx.doi.org/10.1083/jcb.200304014 Text en Copyright © 2003, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Report
Hu, Yue
Fortini, Mark E.
Different cofactor activities in γ-secretase assembly: evidence for a nicastrin–Aph-1 subcomplex
title Different cofactor activities in γ-secretase assembly: evidence for a nicastrin–Aph-1 subcomplex
title_full Different cofactor activities in γ-secretase assembly: evidence for a nicastrin–Aph-1 subcomplex
title_fullStr Different cofactor activities in γ-secretase assembly: evidence for a nicastrin–Aph-1 subcomplex
title_full_unstemmed Different cofactor activities in γ-secretase assembly: evidence for a nicastrin–Aph-1 subcomplex
title_short Different cofactor activities in γ-secretase assembly: evidence for a nicastrin–Aph-1 subcomplex
title_sort different cofactor activities in γ-secretase assembly: evidence for a nicastrin–aph-1 subcomplex
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2199374/
https://www.ncbi.nlm.nih.gov/pubmed/12771124
http://dx.doi.org/10.1083/jcb.200304014
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