Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 γ-secretase complexes Journal Article
| Authors: | Placanica, L.; Tarassishin, L.; Yang, G.; Peethumnongsin, E.; Kim, S. H.; Zheng, H.; Sisodia, S. S.; Li, Y. M. |
| Article Title: | Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 γ-secretase complexes |
| Abstract: | γ-Secretase is known to play a pivotal role in the pathogenesis of Alzheimer disease through production of amyloidogenic Aβ42 peptides. Early onset familial Alzheimer disease mutations in presenilin (PS), the catalytic core of γ-secretase, invariably increase the Aβ42:Aβ40 ratio. However, the mechanism by which these mutations affect γ-secretase complex formation and cleavage specificity is poorly understood. We show that our in vitro assay system recapitulates the effect of PS1 mutations on the Aβ42:Aβ40 ratio observed in cell and animal models. We have developed a series of small molecule affinity probes that allow us to characterize active γ-secretase complexes. Furthermore we reveal that the equilibrium of PS1- and PS2-containing active complexes is dynamic and altered by overexpression of Pen2 or PS1 mutants and that formation of PS2 complexes is positively correlated with increased Aβ42:Aβ40 ratios. These data suggest that perturbations to γ-secretase complex equilibrium can have a profound effect on enzyme activity and that increased PS2 complexes along with mutated PS1 complexes contribute to an increased Aβ42:Aβ40 ratio. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | controlled study; protein expression; human cell; nonhuman; mutant protein; animal cell; mouse; animals; mice; protein protein interaction; cell line; membrane proteins; enzyme activity; hela cells; animalia; amines; gene knock-in techniques; animal cell culture; enzyme structure; alzheimer disease; amyloid precursor protein secretases; active complexes; animal models; catalytic cores; cleavage specificities; dynamic equilibrium; in cells; in-vitro assays; over expressions; presenilin; secretase; secretase complexes; small molecules; gamma secretase; presenilin 1; presenilin 2; biotinylation; biotin; flavin-adenine dinucleotide; presenilin-1; presenilin-2 |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 284 |
| Issue: | 5 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2009-01-30 |
| Start Page: | 2967 |
| End Page: | 2977 |
| Language: | English |
| DOI: | 10.1074/jbc.M807269200 |
| PUBMED: | 19036728 |
| PROVIDER: | scopus |
| PMCID: | PMC2631949 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 10" - "Export Date: 30 November 2010" - "CODEN: JBCHA" - "Source: Scopus" |
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