title: Presenilin transmembrane domain 8 conserved AXXXAXXXG motifs are required for the activity of the γ-secretase complex.
abstract: Understanding the molecular mechanisms controlling the physiological and pathological activity of γ-secretase represents a challenging task in Alzheimer disease research. The assembly and proteolytic activity of this enzyme require the correct interaction of the 19 transmembrane domains (TMDs) present in its four subunits, including presenilin (PS1 or PS2), the γ-secretase catalytic core. GXXXG and GXXXG-like motifs are critical for TMDs interactions as well as for protein folding and assembly. The GXXXG motifs on γ-secretase subunits (e.g. APH-1) or on γ-secretase substrates (e.g. APP) are known to be involved in γ-secretase assembly and in Aβ peptide production, respectively. We identified on PS1 and PS2 TMD8 two highly conserved AXXXAXXXG motifs. The presence of a mutation causing an inherited form of Alzheimer disease (familial Alzheimer disease) in the PS1 motif suggested their involvement in the physiopathological configuration of the γ-secretase complex. In this study, we targeted the role of these motifs on TMD8 of PSs, focusing on their role in PS assembly and catalytic activity. Each motif was mutated, and the impact on complex assembly, activity, and substrate docking was monitored. Different amino acid substitutions on the same motif resulted in opposite effects on γ-secretase activity, without affecting the assembly or significantly impairing the maturation of the complex. Our data suggest that AXXXAXXXG motifs in PS TMD8 are key determinants for the conformation of the mature γ-secretase complex, participating in the switch between the physiological and pathological functional conformations of the γ-secretase.
authors.affiliation: From the Institute of Neuroscience.
authors.forename: Claudia
authors.initials: C
authors.lastname: Marinangeli
authors.affiliation: From the Institute of Neuroscience.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Tasiaux
authors.affiliation: From the Institute of Neuroscience.
authors.forename: Rémi
authors.initials: R
authors.lastname: Opsomer
authors.affiliation: the Louvain Drug Research Institute, and.
authors.forename: Salim
authors.initials: S
authors.lastname: Hage
authors.affiliation: From the Institute of Neuroscience.
authors.forename: Alejandro O
authors.initials: AO
authors.lastname: Sodero
authors.affiliation: From the Institute of Neuroscience.
authors.forename: Ilse
authors.initials: I
authors.lastname: Dewachter
authors.affiliation: From the Institute of Neuroscience.
authors.forename: Jean Noël
authors.initials: JN
authors.lastname: Octave
authors.affiliation: the Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794-5215.
authors.forename: Steven O
authors.initials: SO
authors.lastname: Smith
authors.affiliation: the de Duve Institute and Ludwig Institute for Cancer Research, Université Catholique de Louvain, Brussels 1200, Belgium and.
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.affiliation: From the Institute of Neuroscience, pascal.kienlen-campard@uclouvain.be.
authors.forename: Pascal
authors.initials: P
authors.lastname: Kienlen-Campard
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D017124:Conserved Sequence; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D053764:Presenilin-1 / Q000737:chemistry / Q000378:metabolism*; D053766:Presenilin-2 / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D053764:Presenilin-1; D053766:Presenilin-2; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer Disease; Amyloid Precursor Protein (APP); Notch Receptor; Presenilin; Transmembrane Domain; gamma-Secretase