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. Copyright © 2006 Society for Neuroscience.
CITATION STYLE
Sato, C., Morohashi, Y., Tomita, T., & Iwatsubo, T. (2006). Structure of the catalytic pore of γ-secretase probed by the accessibility of substituted cysteines. Journal of Neuroscience, 26(46), 12081–12088. https://doi.org/10.1523/JNEUROSCI.3614-06.2006
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