title: 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-mu-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) Angstrom and two at 1.855(2) Angstrom). We were also able to locate a Ni-Ni vector at 3.1(1) Angstrom, which suggests the two Ni(II) centers are contained in a bis-mu-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.
authors.affiliation: Department of Chemistry/216, University of Nevada, Reno, NV 89557, USA. shearer@chem.unr.edu
authors.forename: Jason
authors.initials: J
authors.lastname: Shearer
authors.forename: Pamela
authors.initials: P
authors.lastname: Soh
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000235:genetics; D003300:Copper / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D008280:Magnetics; D015335:Molecular Probes; D008969:Molecular Sequence Data; D009532:Nickel / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D011328:Prions / Q000737:chemistry* / Q000235:genetics; D017510:Protein Folding; D013057:Spectrum Analysis; D014965:X-Rays
chemical_list: D000682:Amyloid; D015335:Molecular Probes; D010446:Peptide Fragments; D011328:Prions; D003300:Copper; D009532:Nickel