A Reassessment of Copper(Ii) Binding in the Full-length Prion Protein.
From: Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UK.
The Biochemical journal
- Publish Date: Nov 2006
- ISSN: 1470-8728
- Volume: 399
- Issue: 3
- Pages: 435-44
- Medium: Internet
- Language: English
- Citation (JAMA): Wells Mark A, Jackson Graham S, Jones Samantha, et al. A Reassessment of Copper(Ii) Binding in the Full-length Prion Protein.. Biochem. J. Nov 2006;399:435-44
Abstract
It has been shown previously that the unfolded N-terminal domain of the prion protein can bind up to six Cu2+ ions in vitro. This domain contains four tandem repeats of the octapeptide sequence PHGGGWGQ, which, alongside the two histidine residues at positions 96 and 111, contribute to its Cu2+ binding properties. At the maximum metal-ion occupancy each Cu2+ is co-ordinated by a single imidazole and deprotonated backbone amide groups. However two recent studies of peptides representing the octapeptide repeat region of the protein have shown, that at low Cu2+ availability, an alternative mode of co-ordination occurs where the metal ion is bound by multiple histidine imidazole groups. Both modes of binding are readily populated at pH 7.4, while mild acidification to pH 5.5 selects in favour of the low occupancy, multiple imidazole binding mode. We have used NMR to resolve how Cu2+ binds to the full-length prion protein under mildly acidic conditions where multiple histidine co-ordination is dominant. We show that at pH 5.5 the protein binds two Cu2+ ions, and that all six histidine residues of the unfolded N-terminal domain and the N-terminal amine act as ligands. These two sites are of sufficient affinity to be maintained in the presence of millimolar concentrations of competing exogenous histidine. A previously unknown interaction between the N-terminal domain and a site on the C-terminal domain becomes apparent when the protein is loaded with Cu2+. Furthermore, the data reveal that sub-stoichiometric quantities of Cu2+ will cause self-association of the prion protein in vitro, suggesting that Cu2+ may play a role in controlling oligomerization in vivo.
Mesh Headings (Keywords): Binding Sites, Copper, Glycine, Histidine, Humans, Hydrogen-Ion Concentration, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Peptide Fragments, Prions, Protein Binding, Protein Conformation, Protein Folding, Protein Structure, Tertiary
Check for Full Text / PubMed Unique Identifier (PMID): 16824036
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.