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
Notes: --- - "Cited By (since 1996): 3" - "Export Date: 20 April 2011" - "CODEN: PNASA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Kwangwook Ahn
    10 Ahn
  2. Yueming Li
    109 Li
  3. Yuan Tian
    16 Tian
  4. Christopher C Shelton
    12 Shelton