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The Journal of Neuroscience, June 11, 2008, 28(24):6264-6271; doi:10.1523/JNEUROSCI.1163-08.2008

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Neurobiology of Disease
The C-Terminal PAL Motif and Transmembrane Domain 9 of Presenilin 1 Are Involved in the Formation of the Catalytic Pore of the -Secretase

Chihiro Sato,^1,2,3 Shizuka Takagi,¹ Taisuke Tomita,^1,3 and Takeshi Iwatsubo^1,2,3

¹Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, and ²Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, and ³Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Bunkyo, Tokyo 113-0033, Japan

Correspondence should be addressed to Dr. Taisuke Tomita, 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

-Secretase is an unusual membrane-embedded protease, which cleaves the transmembrane domains (TMDs) of type I membrane proteins, including amyloid-β precursor protein and Notch receptor. We have previously shown the existence of a hydrophilic pore formed by TMD6 and TMD7 of presenilin 1 (PS1), the catalytic subunit of -secretase, within the membrane by the substituted cysteine accessibility method. Here we analyzed the structure of TMD8, TMD9, and the C terminus of PS1, which encompass the conserved PAL motif and the hydrophobic C-terminal tip, both being critical for the catalytic activity and the formation of the -secretase complex. We found that the amino acid residues around the PAL motif and the extracellular/luminal portion of TMD9 are highly water accessible and located in proximity to the catalytic pore. Furthermore, the region starting from the luminal end of TMD9 toward the C terminus forms an amphipathic -helix-like structure that extends along the interface between the membrane and the extracellular milieu. Competition analysis using -secretase inhibitors revealed that the TMD9 is involved in the initial binding of substrates, as well as in the subsequent catalytic process as a subsite. Our results provide mechanistic insights into the role of TMD9 in the formation of the catalytic pore and the substrate entry, crucial to the unusual mode of intramembrane proteolysis by -secretase.

Key words: Alzheimer's disease; amyloid beta; intramembrane-cleaving protease; presenilin; secretase; substituted cysteine accessibility method; Aβ peptide; structure

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Received March 18, 2008; revised April 23, 2008; accepted May 12, 2008.

Correspondence should be addressed to Dr. Taisuke Tomita, 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

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