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

Area of Science:

• Neuroscience
• Structural Biology
• Biochemistry

Background:

• Amyloid precursor protein (APP) is implicated in synaptic function.
• APP's extracellular E1 domain, including the growth factor-like domain (GFLD) and copper-binding domain (CuBD), mediates trans-directed dimerization.
• Copper's role in APP's synaptic activity is not fully understood.

Purpose of the Study:

• To elucidate the structural basis of copper-mediated APP dimerization.
• To determine the role of copper binding in APP's synaptogenic function.

Main Methods:

• X-ray crystallography to determine the structure of the GFLD-copper complex.
• Coimmunoprecipitation assays to assess APP interactions.
• Site-directed mutagenesis to investigate copper-binding site function.
• Primary neuron-HEK293 co-culture assays to evaluate synaptogenesis.

Main Results:

• The crystal structure reveals copper binding to an extended hairpin loop at the GFLD dimerization interface.
• Copper binding significantly enhances APP interaction and promotes APP cis-/trans-directed dimerization.
• Mutations in copper-binding sites drastically reduce APP dimerization.
• Copper-dependent GFLD binding is essential for APP-mediated synaptogenesis.

Conclusions:

• Copper binding to the GFLD of APP is a prerequisite for APP dimerization and its synaptogenic function.
• Altered copper homeostasis, potentially due to neuronal activity or disease, may impact APP synaptic function.