Spectroscopic Investigation on the Copper Binding Site of the Prion Protein

Transmissible spongiform encephalopathies (TSEs) in mammals are neurodegenerative diseases caused by an infectious agent called prion, which seems to be exclusively composed of the disease-related isoform PrPSc of the cellular prion protein PrPC [1]. Although its function is still the subject of debate, accumulating evidence links PrPC function to its ability to bind Cu2+. Several studies have focused in the interaction of the prion protein with copper in the N-terminal domain of the protein, specifically in the octarepeat region, which consists of four tandem repeats of the sequence PHGGGWGQ. The large flexibility of the unstructured N-terminus so far has made impossible a complete structure determination by NMR. The N-terminus of the prion protein becomes more structured in the presence of divalent copper, but the presence of paramagnetic ion centers limits standard NMR structural analysis because of the fast relaxation of the Cu2+ ion. Therefore, a variety of other spectroscopic techniques has been applied to characterize the copper peptide binding site in the prion protein. Our investigations are addressed to infer the solution-state geometry of the copper binding site in the N-terminus of the PrPC. To investigate the geometry of the peptide-Cu2+ complex, a new method for structure determination of the copper environment was developed. This metho