Functional implications of the presenilin dimerization: Reconstitution of γ-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, Gemma Marfany

Research output: Contribution to journalArticleResearchpeer-review

51 Citations (Scopus)

Abstract

Presenilins are the catalytic components of γ-secretase, an intramembrane-cleaving protease whose substrates include β-amyloid precursor protein (βAPP) 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 Aβ and APP intracellular domain (from βAPP) 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 Aβ peptide generated by the γ-secretase. We and others have previously shown that presenilin homodimerizes and suggested that a presenilin dimer is at the catalytic core of γ-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 γ-secretase activities. In addition, by reconstituting γ-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 Aβ but not Notch intracellular domain, therefore suggesting that specific diaspartyl groups within the presenilin catalytic core of γ-secretase mediate the cleavage of different substrates.
Original languageEnglish
Pages (from-to)36519-36529
JournalJournal of Biological Chemistry
Volume279
DOIs
Publication statusPublished - 27 Aug 2004

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