Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ‐secretase modulators

• Published in: The EMBO journal 2019-06, Vol.38 (12), p.n/a
• Main Authors: Petit, Dieter, Hitzenberger, Manuel, Lismont, Sam, Zoltowska, Katarzyna Marta, Ryan, Natalie S, Mercken, Marc, Bischoff, François, Zacharias, Martin, Chávez‐Gutiérrez, Lucía
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - chemistry; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Amyloid Precursor Protein Secretases - chemistry; Amyloid Precursor Protein Secretases - metabolism; Amyloidogenesis; amyloid‐beta; Animals; Catalysis; Cells, Cultured; Drug discovery; EMBO24; EMBO27; EMBO31; Enzyme Activation; Extracellular Space; HEK293 Cells; Humans; Interface stability; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - metabolism; Mice; Models, Molecular; Modulators; Molecular Docking Simulation; Mutation; Neurodegenerative diseases; Neuromodulation; Neurotoxicity; Nicastrin; Nucleotides; Pathogenesis; Peptides; Pharynx; Presenilin 2; Protein Binding; Protein Interaction Domains and Motifs - physiology; Protein Structure, Quaternary; Proteolysis; Secretase; Structure-Activity Relationship; Substrates; γ‐secretase; γ‐secretase modulators
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.2019101494

γ‐Secretase complexes (GSECs) are multimeric membrane proteases involved in a variety of physiological processes and linked to Alzheimer's disease (AD). Presenilin (PSEN, catalytic subunit), Nicastrin (NCT), Presenilin Enhancer 2 (PEN‐2), and Anterior Pharynx Defective 1 (APH1) are the essential subunits of GSECs. Mutations in PSEN and the Amyloid Precursor Protein (APP) cause early‐onset AD. GSECs successively cut APP to generate amyloid‐β (Aβ) peptides of various lengths. AD‐causing mutations destabilize GSEC‐APP/Aβ n interactions and thus enhance the production of longer Aβs, which elicit neurotoxic events underlying pathogenesis. Here, we investigated the molecular strategies that anchor GSEC and APP/Aβ n during the sequential proteolysis. Our studies reveal that a direct interaction between NCT ectodomain and APP C99 influences the stability of GSEC‐Aβn assemblies and thereby modulates Aβ length. The data suggest a potential link between single‐nucleotide variants in NCSTN and AD risk. Furthermore, our work indicates that an extracellular interface between the protease (NCT, PSEN) and the substrate (APP) represents the target for compounds (GSMs) modulating Aβ length. Our findings may guide future rationale‐based drug discovery efforts. Synopsis γ‐Secretase mediated cleavage of APP defines the length of Aβ peptides. Alzheimer's disease causing mutations destabilize γ‐secretase – APP interactions and thus promote the production of longer, amyloidogenic Aβs. Here, we investigated the molecular strategies securing γ‐secretase – APP interactions. NCT ectodomain establishes a direct, short distance interaction with APP ectodomain. NCT‐APP interface influences the stability of γ‐secretase – APP interactions and thereby modulates Aβ length. NCT ectodomain influences the response towards compounds modulating Aβ length. The data suggest a potential link between single nucleotide variants in NCSTN and AD risk. Graphical Abstract A direct interaction between the gamma secretase subunit Nicastrin and APP regulates the stability and processivity of the γ‐secretase/substrate complex to affect Aβ length and Alzheimer disease pathogenicity.