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J. Biol. Chem., Vol. 283, Issue 19, 12831-12839, May 9, 2008

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Manganese Binding to the Prion Protein^*

Marcus W. Brazier, Paul Davies, Esmie Player, Frank Marken, John H. Viles^¶, and David R. Brown¹

From the Departments of Biology and Biochemistry and Chemistry, University of Bath, Bath BA2 7AY, United Kingdom and ^¶School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom

There is considerable evidence that the prion protein binds copper. However, there have also been suggestions that prion protein (PrP) binds manganese. We used isothermal titration calorimetry to identify the manganese binding sites in wild-type mouse PrP. The protein showed two manganese binding sites with affinities that would bind manganese at concentrations of 63 and 200 µM at pH 5.5. This indicates that PrP binds manganese with affinity similar to other known manganese-binding proteins. Further study indicated that the main manganese binding site is associated with His-95 in the so-called "fifth site" normally associated with copper binding. Additionally, it was shown that occupancy by copper does not prevent manganese binding. Under these conditions, manganese binding resulted in an altered conformation of PrP, displacement of copper, and altered redox chemistry of the metal-protein complex. Cyclic voltammetric measurements suggested a complex redox chemistry involving manganese bound to PrP, whereas copper-bound PrP was able to undergo fully reversible electron cycling. Additionally, manganese binding to PrP converted it to a form able to catalyze aggregation of metal-free PrP. These results further support the notion that manganese binding could cause a conformation change in PrP and trigger changes in the protein similar to those associated with prion disease.

Received for publication, December 3, 2007 , and in revised form, February 27, 2008.

^* This work was supported by funding from the European Commission Quality of Life 5th Framework Programme (Grant QLRT-2001-02723) and the Biotechnology and Biological Sciences Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK. Tel.: 44-1225-383133; Fax: 44-1225-386779; E-mail: bssdrb{at}bath.ac.uk.

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