Structural Models for Cu(II) Bound to the Fragment 92–96 of the Human Prion Protein

• Published in: The journal of physical chemistry. B 2013-01, Vol.117 (3), p.789-799
• Main Authors: Grande-Aztatzi, Rafael, Rivillas-Acevedo, Lina, Quintanar, Liliana, Vela, Alberto
• Format: Article
• Language: English
• Subjects: Binding; Binding Sites; Biological and medical sciences; Biological material (laboratory animals, preparation of biological tracers, etc.); Circular Dichroism; Copper; Copper - chemistry; Copper - metabolism; Electron Spin Resonance Spectroscopy; Fragmentation; Fundamental and applied biological sciences. Psychology; General aspects; Humans; Hydrogen-Ion Concentration; Mathematical models; Prions; Protein Binding; Proteins; PrPC Proteins - chemistry; PrPC Proteins - metabolism; Spectroscopy; Water - chemistry
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/jp310000h

The prion protein (PrPC) binds Cu(II) in its N-terminal region, and it is associated to a group of neurodegenerative diseases termed transmissible spongiform encephalopaties (TSEs). The isoform PrPSc, derived from the normal PrPC, is the pathogenic agent of TSEs. Using spectroscopic techniques (UV–vis absorption, circular dichroism, and electron paramagnetic resonance) and electronic structure calculations, we obtained a structural description for the different pH-dependent binding modes of Cu(II) to the PrP(92–96) fragment. We have also evaluated the possibility of water molecule ligation to the His96-bound copper ion. Geometry-optimized structural models that reproduce the spectroscopic features of these complexes are presented. Two Cu(II) binding modes are relevant at physiological pH: 4N and 3NO equatorial coordination modes; these are best described by models with no participation of water molecules in the coordination sphere of the metal ion. In contrast, the 2N2O and N3O coordination modes that are formed at lower pH involve the coordination of an axial water molecule. This study underscores the importance of including explicit water molecules when modeling copper binding sites in PrPC.