Aβ42 overproduction associated with structural changes in the catalytic pore of γ-secretase: Common effects of Pen-2 N-terminal elongation and fenofibrate

Noriko Isoo, Chihiro Sato, Hiroyuki Miyashita, Mitsuru Shinohara, Nobumasa Takasugi, Yuichi Morohashi, Shoji Tsuji, Taisuke Tomita, Takeshi Iwatsubo

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

γ-Secretase is an atypical aspartyl protease that cleaves amyloid β-precursor protein to generate Aβ peptides that are causative for Alzheimer disease. γ-Secretase is a multimeric membrane protein complex composed of presenilin (PS), nicastrin, Aph-1, and Pen-2. Pen-2 directly binds to transmembrane domain 4 of PS and confers proteolytic activity on γ-secretase, although the mechanism of activation and its role in catalysis remain unknown. Here we show that an addition of amino acid residues to the N terminus of Pen-2 specifically increases the generation of Aβ42, the longer and more aggregable species of Aβ. The effect of the N-terminal elongation of Pen-2 on Aβ42 generation was independent of the amino acid sequences, the expression system and the presenilin species. In vitro γ-secretase assay revealed that Pen-2 directly affects the Aβ42-generating activity of γ-secretase. The elongation of Pen-2 N terminus caused a reduction in the water accessibility of the luminal side of the catalytic pore of PS1 in a similar manner to that caused by an Aβ42-raising γ-secretase modulator, fenofibrate, as determined by substituted cysteine accessibility method. These data suggest a unique mechanism of Aβ42 overproduction associated with structural changes in the catalytic pore of presenilins caused commonly by the N-terminal elongation of Pen-2 and fenofibrate.

Original languageEnglish
Pages (from-to)12388-12396
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number17
DOIs
Publication statusPublished - Apr 27 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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