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The Journal of Neuroscience, November 15, 2006, 26(46):12081-12088; doi:10.1523/JNEUROSCI.3614-06.2006

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Neurobiology of Disease
Structure of the Catalytic Pore of -Secretase Probed by the Accessibility of Substituted Cysteines

Chihiro Sato, Yuichi Morohashi, Taisuke Tomita, and Takeshi Iwatsubo

Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan

Correspondence should be addressed to either of the following: Taisuke Tomita or Takeshi Iwatsubo, Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Email: taisuke{at}mol.f.u-tokyo.ac.jp or Email: iwatsubo{at}mol.f.u-tokyo.ac.jp

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 -secretase, involved in amyloid 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 -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 -secretase resides in a catalytic pore filled with water within the lipid bilayer and is tapered around the catalytic aspartates.

Key words: Alzheimer's disease; intramembrane-cleaving protease; presenilin; substituted cysteine accessibility method; A peptide; proteolysis; structure

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Received Aug. 20, 2006; revised Oct. 9, 2006; accepted Oct. 11, 2006.

Correspondence should be addressed to either of the following: Taisuke Tomita or Takeshi Iwatsubo, Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Email: taisuke{at}mol.f.u-tokyo.ac.jp or Email: iwatsubo{at}mol.f.u-tokyo.ac.jp

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