title: SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production.
abstract: Mutations in the human presenilin genes (PS1 or PS2) have been linked to autosomal dominant, early onset Alzheimer's disease (AD). Presenilins, probably as an essential part of gamma-secretase, modulate gamma-cleavage of the amyloid protein precursor (APP) to the amyloid beta-peptide (Abeta). Mutations in sel-12, a Caenorhabditis elegans presenilin homologue, cause a defect in egg laying that can be suppressed by loss of function mutations in a second gene, SEL-10. SEL-10 protein is a homologue of yeast Cdc4, a member of the SCF (Skp1-Cdc53/CUL1-F-box protein) E2-E3 ubiquitin ligase family. In this study, we show that human SEL-10 interacts with PS1 and enhances PS1 ubiquitination, thus altering cellular levels of unprocessed PS1 and its N- and C-terminal fragments. Co-transfection of sel-10 and APP cDNAs in HEK293 cells leads to an alteration in the metabolism of APP and to an increase in the production of amyloid beta-peptide, the principal component of amyloid plaque in Alzheimer's disease.
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D015801:Helminth Proteins / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity; D053764:Presenilin-1; D011485:Protein Binding / Q000502:physiology; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D016229:Amyloid beta-Peptides; C080443:CDC4 protein, S cerevisiae; D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C513272:Fbxw7 protein, mouse; D015801:Helminth Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; C109554:SEL-10 protein, C elegans; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases