ISBN: 978-83-60043-10-3 - eurobic9

Eurobic9, 2-6 September, 2008, Wrocław, Poland
SL25. Copper Binding to the Prion Protein: a Controversial Issue
M. Remelli a , D. Bacco a , E. Gralka b , R. Guerrini c , H. Kozłowski b , D. Valensin d
a
Dipartimento di Chimica, Università di Ferrara, via L. Borsari 46, 44100, Ferrara, Italy
b
Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383, Wroclaw, Poland
c
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, via Fossato di Mortara 17/19, 44100, Ferrara,
Italy
d
Dipartimento di Chimica, Università di Siena, Via Aldo Moro, 53100, Siena,
e-mail: rmm@unife.it
The prion protein (PrPC) is a cell-surface glycoprotein, mainly expressed in liver and brain; its biological
function is mostly unknown. However, there is class of neurodegenerative disorders, i.e. prion diseases, where
high amounts of a modified isoform of PrPC, named PrPSc (scrapie form), abnormally accumulate in neuronal
cells [1]. The PrPC conversion to PrPSc involves only the secondary and tertiary structure of the protein, but it
deeply modifies its chemical properties; the conformational conversion can be caused by familial mutations,
sporadic and even infectious factors [2]. It has been widely demonstrated that PrPC is able to bind copper ions
[3-6]. It can cooperatively bind four copper ions at its unstructured N-terminal, in the so-called “octarepeat
region” (residues 60–91) [5, 6], while other two binding sites are located in correspondence of His-96 and His-
111 residues [3, 7-9]. In this regard, some points are still under investigation: the relative strength of these
binding sites with reference to both the physiologically relevant ligands and the octarepeat domain of the protein
itself; the possible preference by the CuII ion for His-96 or His-111; the possible simultaneous participation of
both His to copper binding; the complex geometry and the donor atoms; the role played by the other amino
acidic residues surrounding the anchoring site. In order to better clarify these points, some fragments of PrPC,
containing His-96 and/or His-111, and their analogues have been taken as model peptides and investigated by
means of potentiometric, calorimetric, UV-VIS, CD, EPR and NMR spectroscopic techniques.
References:
[1] Prusiner, S.B. Proc. Natl. Acad. Sci. USA 1998, 95, 13363,
[2] Prusiner S.B., N.Engl. J. Med. 2001, 344, 1516
[3] Brown, D. R.; Qin, K.; Herms, J.W.; Madlung, A.; Manson, J.; Strome, R.; Fraser, P.E.; Kruck, T.A.; von
Bohlen, A.; Schulz-Schaeffer, W.; Giese, A.; Westaway D.; Kretzschmar H. Nature, 1997, 390, 684.
[4] Hornshaw MP, McDermott JR, Candy JM, Lakey JH., Biochem. Biophys. Res. Commun. 1995 214:993–99
[5] Stockel J, Safar J, Wallace AC, Cohen FE, Prusiner SB.. Biochemistry 1998 37:7185–93
[6] D. R. Brown and H. Kozlowski, Dalton Trans., 2004, 1907.
[7] Gaggelli, E.; Bernardi, F.; Molteni, E.; Pogni, R.; Valensin, D.; Valensin, G.; Remelli, M.; Łuczkowski, M.;
Kozlowski, H. J. Am. Chem. Soc. 2005, 127, 996
[8] Berti, F.; Gaggelli, E.; Guerrini, R.; Janicka, A.; Kozlowski, H.; Legowska, A.; Miecznikowska, H.;
Migliorini, C.; Pogni, R.; Remelli, M.; Rolka, K.; Valensin, D.; Valensin, G. Chem. Eur. J. 2007, 13, 1991.
[9] Klewpatinond, M.; Davies, P.; Bowen, S.; Brown, D.R.; Viles, J.H. J. Biol. Chem. 2008, 283, 1870.
_____________________________________________________________________
77