PT  - JOURNAL ARTICLE
AU  - Chihiro Sato
AU  - Yuichi Morohashi
AU  - Taisuke Tomita
AU  - Takeshi Iwatsubo
TI  - Structure of the Catalytic Pore of γ-Secretase Probed by the Accessibility of Substituted Cysteines
AID  - 10.1523/JNEUROSCI.3614-06.2006
DP  - 2006 Nov 15
TA  - The Journal of Neuroscience
PG  - 12081--12088
VI  - 26
IP  - 46
4099  - http://www.jneurosci.org/content/26/46/12081.short
4100  - http://www.jneurosci.org/content/26/46/12081.full
SO  - J. Neurosci.2006 Nov 15; 26
AB  - 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 γ-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.