title: Engulfment adapter PTB domain containing 1 interacts with and affects processing of the amyloid-β precursor protein.
abstract: Previous studies identified engulfment adapter phosphotyrosine binding (PTB) domain containing 1 (GULP1) as an NPXY-motif interactor of low-density lipoprotein receptor-related protein 1 (LRP1) and suggested a potential relevance in Alzheimer's disease (AD). Since AD associated proteins amyloid-β A4 precursor protein (APP) and LRP1 were shown to interact with the PTB domain of Fe65 and several other adapters via their intracellular NPXY-motifs, we examined a possible interaction of GULP1 PTB domain with the YENPTY-motif of APP. Here we demonstrate that GULP1 is present in human hippocampal and neocortical neurons. Confocal live cell imaging revealed that coexpressed and endogenous GULP1 colocalizes with APP in the Golgi and endoplasmic reticulum. Analysis of the interacting domains by co-immunoprecipitation of point and deletion mutants revealed that the interaction depends on the PTB domain of GULP1 and the YENPTY-motif of APP. Coexpression of GULP1 affected APP cell surface localization and suppressed generation of Aβ40/42 and sAPPα. Taken together, these data identify GULP1 as a novel neuronal APP interacting protein that alters trafficking and processing of APP.
authors.affiliation: Department of Neurology, Center for Clinical Research, Ulm University, Helmholtzstrasse 8/1, D-89081 Ulm, Germany.
authors.forename: Anja-Silke
authors.initials: AS
authors.lastname: Beyer
authors.forename: Bjoern
authors.initials: B
authors.lastname: von Einem
authors.forename: Daniel
authors.initials: D
authors.lastname: Schwanzar
authors.forename: Ilona E
authors.initials: IE
authors.lastname: Keller
authors.forename: Anke
authors.initials: A
authors.lastname: Hellrung
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.forename: Martin
authors.initials: M
authors.lastname: Ingelsson
authors.forename: Alexandra
authors.initials: A
authors.lastname: Makarova
authors.forename: Meihua
authors.initials: M
authors.lastname: Deng
authors.forename: Ekta S
authors.initials: ES
authors.lastname: Chhabra
authors.forename: Christian
authors.initials: C
authors.lastname: Pröpper
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Böckers
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Christine A F
authors.initials: CA
authors.lastname: von Arnim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D019921:Biotinylation; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C454119:GULP1 protein, human; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human