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This paper just came out from the University of California, Davis.

Researchers used computer modelling of the healthy prion protein to determine some interesting findings. When the back-bone of the prion protein contains copper, it cannot form the beta-strand back-bone identified in the mal-formed prion.


Biophys J. 2006 May 12; [Epub ahead of print] free full text article at www.biophysj.org

A mechanism for copper inhibition of infectious prion conversion.

Cox DL, Pan J, Singh RR.

UC Davis.

We employ ab initio electronic structure calculations to obtain two structural models for copper bound in the strongest binding site of the noninfectious form of the prion protein. The models are compatible with available experimental constraints from electron spin resonance data. The bending of the peptide backbone attendant with the copper binding is not compatible with the requisite straight beta-strand backbone structure for the same sequence contained in two recently proposed models of the prion protein structure in its infectious form. We hypothesize that copper binding at this site is protective against conversion to the infectious form, discuss experimental data which appear to support and conflict with our hypothesis, and propose tests using recombinant prion protein, genetically modified cultured neurons, and transgenic mice.

PMID: 16698781


This compliments Dr. DR Brown's work on copper binding to the healthy prion protein, wherein he identified locations, other than the octameric repeat region, where copper preferentially binds (if it is available). Note, he used two different techniques to confirm his findings.

J Biol Chem. 2005 Dec 30;280(52):42750-8. Epub 2005 Oct 28.

High affinity binding between copper and full-length prion protein identified by two different techniques.

Thompsett AR, Abdelraheim SR, Daniels M, Brown DR.

Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom.

The cellular prion protein is known to be a copper-binding protein. Despite the wide range of studies on the copper binding of PrP, there have been no studies to determine the affinity of the protein on both full-length prion protein and under physiological conditions. We have used two techniques, isothermal titration calorimetry and competitive metal capture analysis, to determine the affinity of copper for wild type mouse PrP and a series of mutants. High affinity copper binding by wild type PrP has been confirmed by the independent techniques indicating the presence of specific tight copper binding sites up to femtomolar affinity. Altogether, four high affinity binding sites of between femto- and nanomolar affinities are located within the octameric repeat region of the protein at physiological pH. A fifth copper binding site of lower affinity than those of the octameric repeat region has been detected in full-length protein. Binding to this site is modulated by the histidine at residue 111. Removal of the octameric repeats leads to the enhancement of affinity of this fifth site and a second binding site outside of the repeat region undetected in the wild type protein. High affinity copper binding allows PrP to compete effectively for copper in the extracellular milieu. The copper binding affinities of PrP have been compared with those of proteins of known function and are of magnitudes compatible with an extracellular copper buffer or an enzymatic function such as superoxide dismutase like activity.

PMID: 16258172
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