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J. Biol. Chem., Vol. 279, Issue 35, 36519-36529, August 27, 2004

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Functional Implications of the Presenilin Dimerization

RECONSTITUTION OF -SECRETASE ACTIVITY BY ASSEMBLY OF A CATALYTIC SITE AT THE DIMER INTERFACE OF TWO CATALYTICALLY INACTIVE PRESENILINS^*

Sara Cervantes, Carlos A. Saura¶||, Esther Pomares, Roser Gonzàlez-Duarte, and Gemma Marfany**

From the Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 645, E-08028 Barcelona, Spain and the ^¶Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Presenilins are the catalytic components of -secretase, an intramembrane-cleaving protease whose substrates include -amyloid precursor protein (APP) and the Notch receptors. These type I transmembrane proteins undergo two distinct presenilin-dependent cleavages within the transmembrane region, which result in the production of A and APP intracellular domain (from APP) and the Notch intracellular domain signaling peptide. Most cases of familial Alzheimer's disease are caused by presenilin mutations, which are scattered throughout the coding sequence. Although the underlying molecular mechanism is not yet known, the familial Alzheimer's disease mutations produce a shift in the ratio of the long and short forms of the A peptide generated by the -secretase. We and others have previously shown that presenilin homodimerizes and suggested that a presenilin dimer is at the catalytic core of -secretase. Here, we demonstrate that presenilin transmembrane domains contribute to the formation of the dimer. In-frame substitution of the hydrophilic loop 1, located between transmembranes I and II, which modulates the interactions within the N-terminal fragment/N-terminal fragment dimer, abolishes both presenilinase and -secretase activities. In addition, by reconstituting -secretase activity from two catalytically inactive presenilin aspartic mutants, we provide evidence of an active diaspartyl group assembled at the interface between two presenilin monomers. Under our conditions, this catalytic group mediates the generation of APP intracellular domain and A but not Notch intracellular domain, therefore suggesting that specific diaspartyl groups within the presenilin catalytic core of -secretase mediate the cleavage of different substrates.

Received for publication, April 30, 2004 , and in revised form, June 22, 2004.

^* This study was funded by Ministerio de Ciencia y Tecnología Grant PM99-0168 (to R. G.-D.) and a New Investigator Research Grant from the Alzheimer's Association (to C. A. S.). 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.

Present address: UCSF Diabetes Center, Parnassus Campus, San Francisco, CA 94143.

^|| Present address: Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain.

^** To whom correspondence should be addressed. Tel.: 34-934021502; Fax: 34-934110969; E-mail: gmarfany{at}ub.edu.

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