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J. Biol. Chem., Vol. 280, Issue 51, 41967-41975, December 23, 2005

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Pen-2 Is Incorporated into the -Secretase Complex through Binding to Transmembrane Domain 4 of Presenilin 1^*

Naoto Watanabe, Taisuke Tomita1, Chihiro Sato, Toshio Kitamura, Yuichi Morohashi, and Takeshi Iwatsubo2

From the Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences and Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

-Secretase is a multimeric membrane protein complex comprised of presenilin (PS), nicastrin (Nct), Aph-1, and Pen-2. It is a member of an atypical class of aspartic proteases that hydrolyzes peptide bonds within the membrane. During the biosynthetic process of the -secretase complex, Nct and Aph-1 form a heterodimeric intermediate complex and bind to the C-terminal region of PS, serving as a stabilizing scaffold for the complex. Pen-2 is then recruited into this trimeric complex and triggers endoproteolysis of PS, conferring -secretase activity. Although the Pen-2 accumulation depends on PS, the binding partner of Pen-2 within the -secretase complex remains unknown. We reconstituted PS1 in Psen1/Psen2 deficient cells by expressing a series of PS1 mutants in which one of the N-terminal six transmembrane domains (TMDs) was swapped with those of CD4 (a type I transmembrane protein) or CLAC-P (a type II transmembrane protein). We report that the proximal two-thirds of TMD4 of PS1, including the conserved Trp-Asn-Phe sequence, are required for its interaction with Pen-2. Using a chimeric CD4 molecule harboring PS1 TMD4, we further demonstrate that the PS1 TMD4 bears a direct binding motif to Pen-2. Pen-2 may contribute to the activation of the -secretase complex by directly binding to the TMD4 of PS1.

Received for publication, August 17, 2005 , and in revised form, October 17, 2005.

^* This work was supported by grants-in-aid from the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) and the Ministry of Education, Science, Culture and Sports for the 21st Century Center of Excellence Program, Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Figs. S1 and S2.

¹ To whom correspondence may be addressed. E-mail: taisuke{at}mol.f.u-tokyo.ac.jp. ² To whom correspondence may be addressed. Tel.: 81-3-5841-4877; Fax: 81-3-5841-4708; E-mail: iwatsubo{at}mol.f.u-tokyo.ac.jp.

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