title: The amyloid precursor protein forms plasmalemmal clusters via its pathogenic amyloid-β domain.
abstract: The amyloid precursor protein (APP) is a large, ubiquitous integral membrane protein with a small amyloid-β (Aβ) domain. In the human brain, endosomal processing of APP produces neurotoxic Aβ-peptides, which are involved in Alzheimer's disease. Here, we show that the Aβ sequence exerts a physiological function when still present in the unprocessed APP molecule. From the extracellular site, Aβ concentrates APP molecules into plasmalemmal membrane protein clusters. Moreover, Aβ stabilization of clusters is a prerequisite for their targeting to endocytic clathrin structures. Therefore, we conclude that the Aβ domain directly mediates a central step in APP trafficking, driving its own conversion into neurotoxic peptides.
authors.affiliation: Department of Membrane Biochemistry, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Schreiber
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fischer
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lang
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002966:Clathrin / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008954:Models, Biological; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D016716:PC12 Cells; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D016564:Amyloid beta-Protein Precursor; D002966:Clathrin; D050505:Mutant Proteins