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

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.

The tonoplast copper transporter COPT5 acts as an exporter and is required for interorgan allocation of copper in Arabidopsis thaliana.

Copper is an essential micronutrient for all organisms because it serves as a cofactor of several proteins involved in electron transfer. Elevated copper concentrations can cause toxic effects and organisms have established suitable mechanisms to regulate the uptake and internal distribution of copper to balance the content at an optimal concentration. In recent studies, a family of copper transporters (COPT) with high homology to other eukaryotic copper transporters (Ctr) has been identified in Arabidopsis thaliana. In this study we clarified the physiological function of COPT5. This carrier is located in the tonoplast and functions as a vacuolar copper exporter. Mutants lacking this transporter have altered copper contents in different organs when compared with wild-type plants. We were able to detect copper accumulation in the root and a decreased copper content in siliques and seeds when the COPT5 gene is mutated by T-DNA insertion. Vacuoles purified from copt5 T-DNA-insertion mutants show remarkably increased copper concentrations compared with wild-type organelles. We assume that on the cellular level COPT5 is important for copper export from the vacuole and on the level of the whole plant it is involved in the interorgan reallocation of copper ions from the root to reproductive organs.