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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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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2003
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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. |
format | Text |
id | pubmed-2199374 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2003 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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