Structure of the catalytic pore of γ-secretase probed by the accessibility of substituted cysteines

Chihiro Sato, Yuichi Morohashi, Taisuke Tomita, Takeshi Iwatsubo

Research output: Contribution to journalArticlepeer-review

134 Scopus citations


Several single-span membrane proteins are cleaved within their transmembrane domains (TMDs) by intramembrane-cleaving proteases, although the structure of the active site executing intramembrane cleavage remains unknown. Here we use the substituted cysteine accessibility method to examine the structure of presenilin-1, a catalytic subunit of α-secretase, involved in amyloid β protein generation in Alzheimer's disease and Notch signaling. We show that TMD6 and TMD7 of presenilin-1 contribute to the formation of a hydrophilic pore within the membrane. Residues at the luminal portion of TMD6 are predicted to form a subsite for substrate or inhibitor binding on the α-helix facing a hydrophilic milieu, whereas those around the GxGD catalytic motif within TMD7 are highly water accessible, suggesting formation of a hydrophilic structure within the pore. Collectively, our data suggest that the active site of γ-secretase resides in a catalytic pore filled with water within the lipid bilayer and is tapered around the catalytic aspartates.

Original languageEnglish
Pages (from-to)12081-12088
Number of pages8
JournalJournal of Neuroscience
Issue number46
StatePublished - Nov 15 2006


  • Alzheimer's disease
  • Intramembrane-cleaving protease
  • Peptide
  • Presenilin
  • Proteolysis
  • Structure
  • Substituted cysteine accessibility method


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