Activation and intrinsic γ-secretase activity of presenilin 1 Journal Article
| Authors: | Ahn, K.; Shelton, C. C.; Tian, Y.; Zhang, X.; Gilchrist, M. L.; Sisodia, S. S.; Li, Y. M. |
| Article Title: | Activation and intrinsic γ-secretase activity of presenilin 1 |
| Abstract: | A complex composed of presenilin (PS), nicastrin, PEN-2, and APH-1 is absolutely required for γ-secretase activity in vivo. Evidence has emerged to suggest a role for PS as the catalytic subunit of γ-secretase, but it has not been established that PS is catalytically active in the absence of associated subunits. We now report that bacterially synthesized, recombinant PS (rPS) reconstituted into liposomes exhibits γ-secretase activity. Moreover, an rPS mutant that lacks a catalytic aspartate residue neither exhibits reconstituted γ-secretase activity nor interacts with a transition-state γ-secretase inhibitor. Importantly, we demonstrate that rPS harboring mutations that cause early onset familial Alzheimer's disease (FAD) lead to elevations in the ratio of Aβ42 to Aβ40 peptides produced from a wild-type APP substrate and that rPS enhances the Aβ42/ Aβ40 peptide ratio from FAD-linked mutant APP substrates, findings that are entirely consistent with the results obtained in in vivo settings. Thus, γ-secretase cleavage specificity is an inherent property of the polypeptide. Finally, we demonstrate that PEN2 is sufficient to promote the endoproteolysis of PS1 to generate the active form of γ-secretase. Thus, we conclusively establish that activated PS is catalytically competent and the bimolecular interaction of PS1 and PEN2 can convert the PS1 zymogen to an active protease. |
| Keywords: | protein degradation; enzyme activation; enzyme activity; alzheimer disease; protein cleavage; enzyme synthesis; gamma secretase inhibitor; gamma secretase; presenilin 1; reconstitution; notch; intermembrane-cleaving proteases; presenilinase |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 107 |
| Issue: | 50 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2010-12-14 |
| Start Page: | 21435 |
| End Page: | 21440 |
| Language: | English |
| DOI: | 10.1073/pnas.1013246107 |
| PROVIDER: | scopus |
| PMCID: | PMC3003001 |
| PUBMED: | 21115843 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 20 April 2011" - "CODEN: PNASA" - "Source: Scopus" |
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