title: Amyloid precursor protein dimerization and synaptogenic function depend on copper binding to the growth factor-like domain.
abstract: Accumulating evidence suggests that the copper-binding amyloid precursor protein (APP) has an essential synaptic function. APP synaptogenic function depends on trans-directed dimerization of the extracellular E1 domain encompassing a growth factor-like domain (GFLD) and a copper-binding domain (CuBD). Here we report the 1.75 Å crystal structure of the GFLD in complex with a copper ion bound with high affinity to an extended hairpin loop at the dimerization interface. In coimmunoprecipitation assays copper binding promotes APP interaction, whereas mutations in the copper-binding sites of either the GFLD or CuBD result in a drastic reduction in APP cis-orientated dimerization. We show that copper is essential and sufficient to induce trans-directed dimerization of purified APP. Furthermore, a mixed culture assay of primary neurons with HEK293 cells expressing different APP mutants revealed that APP potently promotes synaptogenesis depending on copper binding to the GFLD. Together, these findings demonstrate that copper binding to the GFLD of APP is required for APP cis-/trans-directed dimerization and APP synaptogenic function. Thus, neuronal activity or disease-associated changes in copper homeostasis likely go along with altered APP synaptic function.
authors.affiliation: Division of Human Biology and Human Genetics.
authors.forename: Frederik
authors.initials: F
authors.lastname: Baumkötter
authors.affiliation: Division of Human Biology and Human Genetics.
authors.forename: Nadine
authors.initials: N
authors.lastname: Schmidt
authors.affiliation: Molecular Biophysics and.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Vargas
authors.affiliation: Division of Human Biology and Human Genetics.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schilling
authors.affiliation: Division of Human Biology and Human Genetics.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Weber
authors.affiliation: Division of Human Biology and Human Genetics.
authors.forename: Katja
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Molecular Biophysics and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fiedler
authors.affiliation: Heidelberg University Biochemistry Center, University of Heidelberg, D-69120 Heidelberg, Germany, and.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Klug
authors.affiliation: Unit of Virus Host Cell Interactions, International Coeducational Unit 3265, Joseph Fourier University-European Molecular Biology Laboratory-National Center of Scientific Research, F-38042 Grenoble, France.
authors.forename: Jens
authors.initials: J
authors.lastname: Radzimanowski
authors.affiliation: Division of Plant Physiology, University of Kaiserslautern, D-67663 Kaiserslautern, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Nickolaus
authors.affiliation: Molecular Biophysics and.
authors.forename: Sandro
authors.initials: S
authors.lastname: Keller
authors.affiliation: Division of Human Biology and Human Genetics.
authors.forename: Simone
authors.initials: S
authors.lastname: Eggert
authors.affiliation: Heidelberg University Biochemistry Center, University of Heidelberg, D-69120 Heidelberg, Germany, and s.kins@biologie.uni-kl.de klemens.wild@bzh.uni-heidelberg.de.
authors.forename: Klemens
authors.initials: K
authors.lastname: Wild
authors.affiliation: Division of Human Biology and Human Genetics, s.kins@biologie.uni-kl.de klemens.wild@bzh.uni-heidelberg.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kins
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D003300:Copper / Q000378:metabolism*; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D011487:Protein Conformation; D055503:Protein Multimerization
chemical_list: D016564:Amyloid beta-Protein Precursor; D003300:Copper
keywords: Alzheimer's disease; amyloid precursor protein; copper; dimerization; metal homeostasis; synaptogenesis