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J. Biol. Chem., Vol. 280, Issue 13, 12967-12975, April 1, 2005

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Aph-1 Contributes to the Stabilization and Trafficking of the -Secretase Complex through Mechanisms Involving Intermolecular and Intramolecular Interactions^*

Manabu Niimura, Noriko Isoo, Nobumasa Takasugi, Makiko Tsuruoka, Kumiko Ui-Tei, Kaoru Saigo, Yuichi Morohashi, Taisuke Tomita¶||, and Takeshi Iwatsubo||

From the Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences and the Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan

-Secretase cleaves type I transmembrane proteins, including -amyloid precursor protein and Notch, and requires the formation of a protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2 for its activity. Aph-1 is implicated in the stabilization of this complex, although its precise mechanistic role remains unknown. Substitution of the first glycine within the transmembrane GXXXG motif of Aph-1 causes a loss-of-function phenotype in Caenorhabditis elegans. Here, using an untranslated region-targeted RNA interference/rescue strategy in Drosophila Schneider 2 cells, we show that Aph-1 contributes to the assembly of the -secretase complex by multiple mechanisms involving intermolecular and intramolecular interactions depending on or independent of the conserved glycines. Aph-1 binds to nicastrin forming an early subcomplex independent of the conserved glycines within the endoplasmic reticulum. Certain mutations in the conserved GXXXG motif affect the interaction of the Aph-1·nicastrin subcomplex with presenilin that mediates trafficking of the presenilin·Aph-1·nicastrin tripartite complex to the Golgi. The same mutations decrease the stability of Aph-1 polypeptides themselves, possibly by affecting intramolecular associations through the transmembrane domains. Our data suggest that the proper assembly of the Aph-1·nicastrin subcomplex with presenilin is the prerequisite for the trafficking as well as the enzymatic activity of the -secretase complex and that Aph-1 functions as a stabilizing scaffold in the assembly of this complex.

Received for publication, August 26, 2004 , and in revised form, January 3, 2005.

^* This work was supported by grants-in-aid from the Ministry of Education, Science, Culture and Sports for the 21st Century Center of Excellence Program and by the Program for Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency (PMDA), 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.

^¶ Recipient of a postdoctoral fellowship for research abroad from the Japan Society for the Promotion of Science.

^|| To whom correspondence may be addressed: Dept. of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel.: 81-3-5841-4877; Fax: 81-3-5841-4708; E-mail: taisuke{at}mol.f.u-tokyo.ac.jp or iwatsubo{at}mol.f.u-tokyo.ac.jp.

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