Ni K-edge XAS suggests that coordination of Ni II to the unstructured amyloidogenic region of the human prion protein produces a Ni 2 bis-μ-hydroxo dimer

Abstract

Prion diseases are thought to be caused by the misfolding of the ubiquitous neuronal membrane prion protein (PrP) through an unknown mechanism that may involve Cu II coordination to the PrP. Previous work has utilized Ni II as a diamagnetic probe for Cu II coordination [C.E. Jones, M. Klewpatinond, S.R. Abdelraheim, D.R. Brown, J.H. Viles, J. Mol. Biol. 346 (2005) 1393–1407]. Herein we investigate Ni II coordination to the PrP fragment PrP(93–114) (AcN-GGTHSQWNKPSKPKTNMKHMAG) at pH = 10.0 by Ni K-edge X-ray absorption spectroscopy (XAS). We find that two equivalents of Ni II will coordinate to PrP(93–114) by UV/Vis titrations and mass spectrometry. Ni K-edge XAS data is consistent with Ni II ligated by five N/O based ligands (three N/O ligands at 2.01(2) Å and two at 1.855(2) Å). We were also able to locate a Ni–Ni vector at 3.1(1) Å, which suggests the two Ni II centers are contained in a bis-μ-hydroxo dimer. We therefore suggest that Ni II may not be a suitable diamagnetic mimic for Cu II coordination within the PrP since differential coordination modes for the two metals exist.