Specific combinations of presenilins and Aph1s affect the substrate specificity and activity of γ-secretase.
The γ-secretase complex comprises presenilin (PS), nicastrin (NCT), anterior pharynx-defective 1 (Aph1), and presenilin enhancer 2 (Pen2). PS has two homologues, PS1 and PS2. Aph1 has two isoforms, Aph1a and Aph1b, with the former existing as two splice variants Aph1aL and Aph1aS. Each complex consists of one subunit each, resulting in six different γ-secretases. To better understand the functional differences among the γ-secretases, we reconstituted them using a yeast system and compared Notch1-cleavage and amyloid precursor protein (APP)-cleavage activities. Intriguingly, PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4, was cleaved. In HEK cell lines expressing defined γ-secretase subunits, we showed that PS1/Aph1b, PS2/Aph1aL, PS2/Aph1aS and PS2/Aph1b γ-secretase produced amyloid β peptide (Aβ) with a higher Aβ42+Aβ43-to-Aβ40 (Aβ42(43)/Aβ40) ratio than the other γ-secretases. In addition, PS2/Aph1aS γ-secretase produced less Notch intracellular domain (NICD) than did the other 5 γ-secretases. Considering that the Aβ42(43)/Aβ40 ratio is relevant in the pathogenesis of Alzheimer's disease (AD), and that inhibition of Notch cleavage causes severe side effect, these results suggest that the PS2/Aph1aS γ-secretase complex is a potential therapeutic target in AD.
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo 153-8902, Japan; Leibniz Institute on Age Research, Fritz-Lipmann-Institute, Beutenbergstr. 11, Jena, 07745, Germany.
Yoji
Y
Yonemura
Departmentof Molecular and Cell Biology, Graduate School of Agricultural Science Tohoku University, Miyagi 981-8555, Japan.
Eugene
E
Futai
Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Iruma-gun, Saitama, 350-0495, Japan.
Sosuke
S
Yagishita
Leibniz Institute on Age Research, Fritz-Lipmann-Institute, Beutenbergstr. 11, Jena, 07745, Germany.
Christoph
C
Kaether
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo 153-8902, Japan. Electronic address: sishiura@mail.doshisha.ac.jp.
Shoichi
S
Ishiura
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D010450:Endopeptidases; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; D020033:Protein Isoforms; D021122:Protein Subunits; D051880:Receptors, Notch; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C098994:amyloid beta-protein (1-43); C475154:APH1A protein, human; C475155:APH1B protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases
Alzheimer's disease; Aβ; Notch; γ-secretase