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J. Biol. Chem., Vol. 280, Issue 9, 7758-7768, March 4, 2005

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Uncoupled Packaging of Amyloid Precursor Protein and Presenilin 1 into Coat Protein Complex II Vesicles^*

Jinoh Kim, Susan Hamamoto, Mariella Ravazzola, Lelio Orci, and Randy Schekman¶

From the Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, California 94720 and Department of Cellular Physiology and Metabolism, University of Geneva Medical School, 1211 Geneva 4, Switzerland

Mutant forms of presenilin (PS) 1 and 2 and amyloid precursor protein (APP) lead to familial Alzheimer's disease. Several reports indicate that PS may modulate APP export from the endoplasmic reticulum (ER). To develop a test of this possibility, we reconstituted the capture of APP and PS1 in COPII (coat protein complex II) vesicles formed from ER membranes in permeabilized cultured cells. The recombinant forms of mammalian COPII proteins were active in a reaction that measures coat subunit assembly and coated vesicle budding on chemically defined synthetic liposomes. However, the recombinant COPII proteins were not active in cargo capture and vesicle budding from microsomal membranes. In contrast, rat liver cytosol was active in stimulating the sorting and packaging of APP, PS1, and p58 (an itinerant ER to Golgi marker protein) into transport vesicles from donor ER membranes. Budding was stimulated in dilute cytosol by the addition of recombinant COPII proteins. Fractionation of the cytosol suggested one or more additional proteins other than the COPII subunits may be essential for cargo selection or vesicle formation from the mammalian ER membrane. The recombinant Sec24C specifically recognized the APP C-terminal region for packaging. Titration of Sarla distinguished the packaging requirements of APP and PS1. Furthermore, APP packaging was not affected by deletion of PS1 or PS1 and 2, suggesting APP and PS1 trafficking from the ER are normally uncoupled.

Received for publication, September 27, 2004 , and in revised form, December 27, 2004.

^* The work was supported by funds provided by the Adler and Fidelity Foundations and the Howard Hughes Medical Institute (to R. S.) and the Swiss National Fund (to L. O.). 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.

^¶ To whom correspondence should be addressed: Dept. of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720. Tel.: 510-642-5686; Fax: 510-642-7846; E-mail: schekman{at}berkeley.edu.

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