Deciphering Copper Coordination in the Mammalian Prion Protein Amyloidogenic Domain

• Published in: Biophysical journal 2020-02, Vol.118 (3), p.676-687
• Main Authors: Salzano, Giulia, Brennich, Martha, Mancini, Giordano, Tran, Thanh Hoa, Legname, Giuseppe, D’Angelo, Paola, Giachin, Gabriele
• Format: Article
• Language: English
• Subjects: Amyloid; Animals; Binding Sites; Copper; Prion Proteins - genetics; Prions; Sheep
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/j.bpj.2019.12.025

Prions are pathological isoforms of the cellular prion protein that is responsible for transmissible spongiform encephalopathies (TSE). Cellular prion protein interacts with copper, Cu(II), through octarepeat and nonoctarepeat (non-OR) binding sites. The molecular details of Cu(II) coordination within the non-OR region are not well characterized yet. By the means of small angle x-ray scattering and x-ray absorption spectroscopic methods, we have investigated the effect of Cu(II) on prion protein folding and its coordination geometries when bound to the non-OR region of recombinant prion proteins (recPrP) from mammalian species considered resistant or susceptible to TSE. As the prion resistant model, we used ovine recPrP (OvPrP) carrying the protective polymorphism at residues A136, R154, and R171, whereas as TSE-susceptible models, we employed OvPrP with V136, R154, and Q171 polymorphism and bank vole recPrP. Our analysis reveals that Cu(II) affects the structural plasticity of the non-OR region, leading to a more compacted conformation. We then identified two Cu(II) coordination geometries: in the type 1 coordination observed in OvPrP at residues A136, R154, and R171, the metal is coordinated by four residues; conversely, the type 2 coordination is present in OvPrP with V136, R154, and Q171 and bank vole recPrP, where Cu(II) is coordinated by three residues and by one water molecule, making the non-OR region more exposed to the solvent. These changes in copper coordination affect the recPrP amyloid aggregation. This study may provide new insights into the molecular mechanisms governing the resistance or susceptibility of certain species to TSE.