title: Soluble amyloid-β precursor protein binds its cell surface receptor in a cooperative fashion with glypican and syndecan proteoglycans.
abstract: Proteolytic processing of amyloid-β precursor protein (APP) generates the amyloid-β peptide, which plays a central role in Alzheimer disease. The physiological function of APP and its proteolytic fragments, however, remains barely understood. Here we show that, on the basis of its binding characteristics, the secreted ectodomain of APP (sAPP) is a new member of the heparin-binding growth factor superfamily. Like other of its members, sAPP binds in a bivalent manner to the plasma membrane with two different subdomains. The N-terminal growth-factor-like domain (GFLD) is necessary and sufficient for protein-receptor binding, whereas the E2-domain mediates interaction with membrane-anchored heparan sulfate proteoglycans (HSPGs). The membrane-anchored HSPGs function as low-affinity co-receptors for sAPP and enhance the affinity to the sAPP receptor. Our findings provide a solid basis for the further identification of this receptor.
authors.affiliation: VIB Center for the Biology of Disease, VIB, B-3000 Leuven, Belgium.
authors.forename: Constanze
authors.initials: C
authors.lastname: Reinhard
authors.forename: Marianne
authors.initials: M
authors.lastname: Borgers
authors.forename: Guido
authors.initials: G
authors.lastname: David
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D053673:Glypicans / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D053669:Syndecan-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053673:Glypicans; D011956:Receptors, Cell Surface; C508246:Sdc2 protein, mouse; D053669:Syndecan-2
keywords: APP-receptor; Alzheimer; Amyloid precursor protein (APP); Ectodomain of APP; Growth factor; Proteoglycan; sAPP