| http://purl.uniprot.org/citations/15537629 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/15537629 | http://www.w3.org/2000/01/rdf-schema#comment | "Macromolecular complexes containing presenilins (PS), nicastrin (NCT), APH-1, and PEN-2 mediate the gamma-secretase cleavage of the beta-amyloid precursor protein and Notch. APH-1 and NCT stabilize the PS1 holoprotein, whereas PEN-2 is critical for endoproteolysis of PS1. To define the structural domains of PEN-2 that are necessary for mediating PS1 endoproteolysis and gamma-secretase activity, we coexpressed APH-1, NCT, and PS1 together with a series of PEN-2 mutants, which harbored deletions in hydrophilic segments, or chimeric PEN-2 molecules that contained heterologous transmembrane domains (TMDs). We now report that with the exception of the PEN-2 variants with deletions proximal to the TMDs, the vast majority of the deletion variants were functional. Mutants that were nonfunctional were also unstable but were rescued by transposition of a heterologous sequence containing conservative amino acid substitutions into the deleted region. Notably, the carboxyl-terminal hydrophilic domain of PEN-2 was dispensable for promoting PS1 endoproteolysis but was critical for stabilizing the resulting PS1 derivatives. More importantly, we demonstrated that a chimeric PEN-2 with a replacement of the TMD2 with the TMD1 from sterol regulatory element binding protein 1 (SREBP-1) is fully functional but that a chimeric PEN-2 with a replacement of the TMD1 with the TMD2 from SREBP-1 is not. The function of this latter chimera was rescued by the replacement of the proximal two-thirds of the SREBP-1 TMD2 with the proximal two-thirds of the authentic TMD1 from PEN-2. These results suggest that the proximal two-thirds of the PEN-2 TMD1 is functionally important for endoproteolysis of PS1 holoproteins and the generation of PS1 fragments, essential components of the gamma-secretase complex."xsd:string |
| http://purl.uniprot.org/citations/15537629 | http://purl.org/dc/terms/identifier | "doi:10.1074/jbc.m412404200"xsd:string |
| http://purl.uniprot.org/citations/15537629 | http://purl.uniprot.org/core/author | "Kim S.H."xsd:string |
| http://purl.uniprot.org/citations/15537629 | http://purl.uniprot.org/core/author | "Sisodia S.S."xsd:string |
| http://purl.uniprot.org/citations/15537629 | http://purl.uniprot.org/core/date | "2005"xsd:gYear |
| http://purl.uniprot.org/citations/15537629 | http://purl.uniprot.org/core/name | "J Biol Chem"xsd:string |
| http://purl.uniprot.org/citations/15537629 | http://purl.uniprot.org/core/pages | "1992-2001"xsd:string |
| http://purl.uniprot.org/citations/15537629 | http://purl.uniprot.org/core/title | "A sequence within the first transmembrane domain of PEN-2 is critical for PEN-2-mediated endoproteolysis of presenilin 1."xsd:string |
| http://purl.uniprot.org/citations/15537629 | http://purl.uniprot.org/core/volume | "280"xsd:string |
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