title: Abeta42 overproduction associated with structural changes in the catalytic pore of gamma-secretase: common effects of Pen-2 N-terminal elongation and fenofibrate.
abstract: gamma-Secretase is an atypical aspartyl protease that cleaves amyloid beta-precursor protein to generate Abeta peptides that are causative for Alzheimer disease. gamma-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 gamma-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 Abeta42, the longer and more aggregable species of Abeta. The effect of the N-terminal elongation of Pen-2 on Abeta42 generation was independent of the amino acid sequences, the expression system and the presenilin species. In vitro gamma-secretase assay revealed that Pen-2 directly affects the Abeta42-generating activity of gamma-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 Abeta42-raising gamma-secretase modulator, fenofibrate, as determined by substituted cysteine accessibility method. These data suggest a unique mechanism of Abeta42 overproduction associated with structural changes in the catalytic pore of presenilins caused commonly by the N-terminal elongation of Pen-2 and fenofibrate.
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Isoo
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyashita
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shinohara
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Takasugi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Morohashi
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D002460:Cell Line; D004330:Drosophila; D004789:Enzyme Activation / Q000187:drug effects; D011345:Fenofibrate / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D010446:Peptide Fragments / Q000096:biosynthesis*; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D000960:Hypolipidemic Agents; D046912:Multiprotein Complexes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D011345:Fenofibrate