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J. Biol. Chem., Vol. 281, Issue 36, 26569-26577, September 8, 2006

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Presenilin-1 Maintains a Nine-Transmembrane Topology throughout the Secretory Pathway^*

Dragana Spasic¹, Alexandra Tolia, Katleen Dillen², Veerle Baert, Bart De Strooper, Stefan Vrijens, and Wim Annaert³

From the Laboratories of Membrane Trafficking and Neuronal Cell Biology, Department of Human Genetics, Gasthuisberg, Katholieke Universiteit Leuven/VIB11, B-3000 Leuven, Belgium

Presenilin-1 is a polytopic membrane protein that assembles with nicastrin, PEN-2, and APH-1 into an active -secretase complex required for intramembrane proteolysis of type I transmembrane proteins. Although essential for a correct understanding of structure-function relationships, its exact topology remains an issue of strong controversy. We revisited presenilin-1 topology by inserting glycosylation consensus sequences in human PS1 and expressing the obtained mutants in a presenilin-1 and 2 knock-out background. Based on the glycosylation status of these variants we provide evidence that presenilin-1 traffics through the Golgi after a conformational change induced by complex assembly. Based on our glycosylation variants of presenilin-1 we hypothesize that complex assembly occurs during transport between the endoplasmic reticulum and the Golgi apparatus. Furthermore, our data indicate that presenilin-1 has a nine-transmembrane domain topology with the COOH terminus exposed to the lumen/extracellular surface. This topology is independently underscored by lysine mutagenesis, cell surface biotinylation, and cysteine derivation strategies and is compatible with the different physiological functions assigned to presenilin-1.

Received for publication, January 20, 2006 , and in revised form, July 5, 2006.

^* This work was supported in part by Flanders Interuniversity Institute for Biotechnology (VIB) and Fonds voor Wetenschappelijk Onderzoek (FWO)-Vlaanderen (G.0243.04), KULeuven (GOA/2004/12), and IARF-ISAO2002/IARF2004. 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 supplemental Fig. S1.

¹ Recipient of a KULeuven fellowship in the framework of the Central and Eastern European initiatives (OE).

² Recipient of an FWO aspirant doctoral fellowship.

³ To whom correspondence should be addressed: Laboratory for Membrane Trafficking, Rm. 9.696; Dept. and Center of Human Genetics, KULeuven/VIB11, Gasthuisberg, B-3000 Leuven, Belgium. Tel.: 32-16-330520; Fax: 32-16-330522; E-mail: Willem.Annaert{at}med.kuleuven.be.

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