2. Academic Validation
  3. Amyloid precursor protein dimerization and synaptogenic function depend on copper binding to the growth factor-like domain

Amyloid precursor protein dimerization and synaptogenic function depend on copper binding to the growth factor-like domain

  • J Neurosci. 2014 Aug 13;34(33):11159-72. doi: 10.1523/JNEUROSCI.0180-14.2014.
Frederik Baumkötter 1,  Nadine Schmidt 1,  Carolyn Vargas 2,  Sandra Schilling 1,  Rebecca Weber 1,  Katja Wagner 1,  Sebastian Fiedler 2,  Wilfried Klug 3,  Jens Radzimanowski 4,  Sebastian Nickolaus 5,  Sandro Keller 2,  Simone Eggert 1,  Klemens Wild 6,  Stefan Kins 7
Affiliations

Affiliations

  • 1 Division of Human Biology and Human Genetics.
  • 2 Molecular Biophysics and.
  • 3 Heidelberg University Biochemistry Center, University of Heidelberg, D-69120 Heidelberg, Germany, and.
  • 4 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.
  • 5 Division of Plant Physiology, University of Kaiserslautern, D-67663 Kaiserslautern, Germany.
  • 6 Heidelberg University Biochemistry Center, University of Heidelberg, D-69120 Heidelberg, Germany, and s.kins@biologie.uni-kl.de klemens.wild@bzh.uni-heidelberg.de.
  • 7 Division of Human Biology and Human Genetics, s.kins@biologie.uni-kl.de klemens.wild@bzh.uni-heidelberg.de.
PMID: 25122912 DOI: 10.1523/JNEUROSCI.0180-14.2014
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.

Keywords

Alzheimer's disease; amyloid precursor protein; copper; dimerization; metal homeostasis; synaptogenesis.

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