Familial Alzheimer disease presenilin-1 mutations alter the active site conformation of γ-secretase Journal Article

   


Authors: Chau, D. M.; Crump, C. J.; Villa, J. C.; Scheinberg, D. A.; Li, Y. M.
Article Title: Familial Alzheimer disease presenilin-1 mutations alter the active site conformation of γ-secretase
Abstract: Presenilin-1 (PS1) is the catalytic subunit of γ-secretase, and mutations in this protein cause familial Alzheimer Disease (FAD). However, little is known about how these mutations affect the active site of γ-secretase. Here, we show that PS1 mutations alter the S2 subsite within the active site of γ-secretase using a multiple photoaffinity probe approach called "photophore walking." Moreover, we developed a unique in vitro assay with a biotinylated recombinant Notch1 substrate and demonstrated that PS1 FAD mutations directly and significantly reduced γ-secretase activity for Notch1 cleavage. Substitution of the Notch Cys-1752 residue, which interacts with the S2 subsite, with Val, Met, or Ile has little effect on wild-type PS1 but leads to more efficient substrates for mutant PS1s. This study indicates that alteration of this S2 subsite plays an important role in determining the activity and specificity of γ-secretase for APP and Notch1 processing, which provides structural basis and insights on how certain PS1 FAD mutations lead toAD pathogenesis. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
Keywords: controlled study; gene mutation; human cell; mutation, missense; pathogenesis; nonhuman; mouse; animal tissue; amino acid substitution; receptor, notch1; in vitro study; enzyme activity; enzyme substrate; hela cell; wild type; anura; protein processing; wild types; isoleucine; protein structure; enzyme specificity; catalytic domain; alzheimer disease; methionine; protein cleavage; cysteine; substrates; valine; amyloid precursor protein; notch1 receptor; amyloid precursor protein secretases; in-vitro assays; gamma secretase; presenilin 1; biotinylation; presenilin-1; enzyme active site; photoaffinity labeling; enzyme conformation; neurodegenerative diseases; structural basis; hek293 cells; secretases; active site; catalytic subunits; genetic diseases, inborn; photoaffinity; fad gene; ps1 gene
Journal Title: Journal of Biological Chemistry
Volume: 287
Issue: 21
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2012-05-18
Start Page: 17288
End Page: 17296
Language: English
DOI: 10.1074/jbc.M111.300483
PROVIDER: scopus
PUBMED: 22461631
PMCID: PMC3366784
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84861203709&partnerID=40&md5=99c9a54dd401e28412046817badc1992
Notes: --- - "Export Date: 4 June 2012" - "CODEN: JBCHA" - "Source: Scopus"
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MSK Authors
  1. David Scheinberg
    499 Scheinberg
  2. Yueming Li
    132 Li
  3. Christina J Crump
    12 Crump
  4. Jennifer W Chien
    4 Chien
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