title: Interactome analyses of mature γ-secretase complexes reveal distinct molecular environments of presenilin (PS) paralogs and preferential binding of signal peptide peptidase to PS2.
abstract: γ-Secretase plays a pivotal role in the production of neurotoxic amyloid β-peptides (Aβ) in Alzheimer disease (AD) and consists of a heterotetrameric core complex that includes the aspartyl intramembrane protease presenilin (PS). The human genome codes for two presenilin paralogs. To understand the causes for distinct phenotypes of PS paralog-deficient mice and elucidate whether PS mutations associated with early-onset AD affect the molecular environment of mature γ-secretase complexes, quantitative interactome comparisons were undertaken. Brains of mice engineered to express wild-type or mutant PS1, or HEK293 cells stably expressing PS paralogs with N-terminal tandem-affinity purification tags served as biological source materials. The analyses revealed novel interactions of the γ-secretase core complex with a molecular machinery that targets and fuses synaptic vesicles to cellular membranes and with the H(+)-transporting lysosomal ATPase macrocomplex but uncovered no differences in the interactomes of wild-type and mutant PS1. The catenin/cadherin network was almost exclusively found associated with PS1. Another intramembrane protease, signal peptide peptidase, predominantly co-purified with PS2-containing γ-secretase complexes and was observed to influence Aβ production.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Ontario M5S3H2, Canada.
authors.forename: Amy Hye Won
authors.initials: AH
authors.lastname: Jeon
authors.forename: Christopher
authors.initials: C
authors.lastname: Böhm
authors.forename: Fusheng
authors.initials: F
authors.lastname: Chen
authors.forename: Hairu
authors.initials: H
authors.lastname: Huo
authors.forename: Xueying
authors.initials: X
authors.lastname: Ruan
authors.forename: Carl He
authors.initials: CH
authors.lastname: Ren
authors.forename: Keith
authors.initials: K
authors.lastname: Ho
authors.forename: Seema
authors.initials: S
authors.lastname: Qamar
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
authors.forename: Howard T J
authors.initials: HT
authors.lastname: Mount
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: Gerold
authors.initials: G
authors.lastname: Schmitt-Ulms
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D051177:Catenins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D015820:Cadherins; D051177:Catenins; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D053829:Amyloid Precursor Protein Secretases; D012697:Serine Endopeptidases; C026515:type I signal peptidase; D025262:Vacuolar Proton-Translocating ATPases
keywords: Alzheimers Disease; Interactome; Mass Spectrometry (MS); Presenilin; Proteomics; Secretases; Transgenic