rdf:type |
|
lifeskim:mentions |
|
pubmed:issue |
13
|
pubmed:dateCreated |
2005-3-28
|
pubmed:abstractText |
Gamma-secretase cleaves type I transmembrane proteins, including beta-amyloid precursor protein and Notch, and requires the formation of a protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2 for its activity. Aph-1 is implicated in the stabilization of this complex, although its precise mechanistic role remains unknown. Substitution of the first glycine within the transmembrane GXXXG motif of Aph-1 causes a loss-of-function phenotype in Caenorhabditis elegans. Here, using an untranslated region-targeted RNA interference/rescue strategy in Drosophila Schneider 2 cells, we show that Aph-1 contributes to the assembly of the gamma-secretase complex by multiple mechanisms involving intermolecular and intramolecular interactions depending on or independent of the conserved glycines. Aph-1 binds to nicastrin forming an early subcomplex independent of the conserved glycines within the endoplasmic reticulum. Certain mutations in the conserved GXXXG motif affect the interaction of the Aph-1.nicastrin subcomplex with presenilin that mediates trafficking of the presenilin.Aph-1.nicastrin tripartite complex to the Golgi. The same mutations decrease the stability of Aph-1 polypeptides themselves, possibly by affecting intramolecular associations through the transmembrane domains. Our data suggest that the proper assembly of the Aph-1.nicastrin subcomplex with presenilin is the prerequisite for the trafficking as well as the enzymatic activity of the gamma-secretase complex and that Aph-1 functions as a stabilizing scaffold in the assembly of this complex.
|
pubmed:language |
eng
|
pubmed:journal |
|
pubmed:citationSubset |
IM
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/3' Untranslated Regions,
http://linkedlifedata.com/resource/pubmed/chemical/APH-1 protein, C elegans,
http://linkedlifedata.com/resource/pubmed/chemical/Amyloid Precursor Protein Secretases,
http://linkedlifedata.com/resource/pubmed/chemical/Caenorhabditis elegans Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Complementary,
http://linkedlifedata.com/resource/pubmed/chemical/Drosophila Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Glycine,
http://linkedlifedata.com/resource/pubmed/chemical/Green Fluorescent Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Homeodomain Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides
|
pubmed:status |
MEDLINE
|
pubmed:month |
Apr
|
pubmed:issn |
0021-9258
|
pubmed:author |
|
pubmed:issnType |
Print
|
pubmed:day |
1
|
pubmed:volume |
280
|
pubmed:owner |
NLM
|
pubmed:authorsComplete |
Y
|
pubmed:pagination |
12967-75
|
pubmed:dateRevised |
2006-11-15
|
pubmed:meshHeading |
pubmed-meshheading:15644323-3' Untranslated Regions,
pubmed-meshheading:15644323-Amino Acid Motifs,
pubmed-meshheading:15644323-Amyloid Precursor Protein Secretases,
pubmed-meshheading:15644323-Animals,
pubmed-meshheading:15644323-Caenorhabditis elegans,
pubmed-meshheading:15644323-Caenorhabditis elegans Proteins,
pubmed-meshheading:15644323-Cell Line,
pubmed-meshheading:15644323-Cell Membrane,
pubmed-meshheading:15644323-DNA, Complementary,
pubmed-meshheading:15644323-Drosophila Proteins,
pubmed-meshheading:15644323-Drosophila melanogaster,
pubmed-meshheading:15644323-Endopeptidases,
pubmed-meshheading:15644323-Endoplasmic Reticulum,
pubmed-meshheading:15644323-Genetic Complementation Test,
pubmed-meshheading:15644323-Glycine,
pubmed-meshheading:15644323-Golgi Apparatus,
pubmed-meshheading:15644323-Green Fluorescent Proteins,
pubmed-meshheading:15644323-Homeodomain Proteins,
pubmed-meshheading:15644323-Immunoprecipitation,
pubmed-meshheading:15644323-Membrane Proteins,
pubmed-meshheading:15644323-Models, Biological,
pubmed-meshheading:15644323-Mutation,
pubmed-meshheading:15644323-Peptides,
pubmed-meshheading:15644323-Phenotype,
pubmed-meshheading:15644323-Plasmids,
pubmed-meshheading:15644323-Protein Binding,
pubmed-meshheading:15644323-Protein Structure, Tertiary,
pubmed-meshheading:15644323-RNA Interference
|
pubmed:year |
2005
|
pubmed:articleTitle |
Aph-1 contributes to the stabilization and trafficking of the gamma-secretase complex through mechanisms involving intermolecular and intramolecular interactions.
|
pubmed:affiliation |
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan.
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|