Cu2 Binding to the Neurotoxic Prion Protein Fragment

The fibrillogenic peptide comprising residues 106-126 of the mammalian prion protein is largely used to study the neurotoxic mechanisms related to prion diseases [41-43]. The hydrophobic core sequence (PrP 113-122, AGAAAAGAVV) is basic for the regulation of neurotoxicity although it is not sufficient for a complete neurotoxic effect [44]. There is growing evidence demonstrating that transition metal ions, especially Cu2+ ions, may affect the aggregation process of

Figure 9. Distribution profiles of competition between 1-Hex (= 1-HP) (dotted line) and 4-Hex (= 4-HP) (dashed line) in coordination of four Cu2+. [Cu2+] = 5 x 10-4 M; ligand (1-Hex) to metal to ligand (4-Hex) ratio 4:4:1. (Reproduced by permission from [40]).

Figure 9. Distribution profiles of competition between 1-Hex (= 1-HP) (dotted line) and 4-Hex (= 4-HP) (dashed line) in coordination of four Cu2+. [Cu2+] = 5 x 10-4 M; ligand (1-Hex) to metal to ligand (4-Hex) ratio 4:4:1. (Reproduced by permission from [40]).

Figure 10. Distribution profiles of competition between human octapeptide (Ac-PHGGGWGQ-NH2) 1-Oct (= 1-OP) and chicken 1-Hex (= 1-HP) in coordination of one Cu2+; [Cu2+] = 1 x 10-3M; ligand (1-Oct) to metal to ligand (1-Hex) ratio 1:1:1. (Reproduced by permission from [40]).

Figure 10. Distribution profiles of competition between human octapeptide (Ac-PHGGGWGQ-NH2) 1-Oct (= 1-OP) and chicken 1-Hex (= 1-HP) in coordination of one Cu2+; [Cu2+] = 1 x 10-3M; ligand (1-Oct) to metal to ligand (1-Hex) ratio 1:1:1. (Reproduced by permission from [40]).

PrP 106-126 [45]. His111 was usually assumed to act as the main coordination site for Cu2+ ions. The involvement of methionines (109 and 112) was also suggested [45,46], but all later studies did not reach any evidence of copper binding to the methionine sulfur [27,34,47-49]. His111 acts as the anchoring site for the Cu2+ ion, which may also coordinate to the adjacent amide nitrogen donors [34,47,48]. Neurotoxic properties of the PrP 106-126 fragment are the same for the N-terminal protected and unprotected peptide, but binding abilities towards Cu2+ may be different in these two cases. PrP 106-126 with unprotected N-terminal Lys involves its amino group in metal ion coordination [47,48]. Cu2+ binds the N-terminal and His111 imidazole nitrogen donors and the terminal carboxylate is stabilizing the coordination sphere through ionic interactions (Figure 11) [48]. The involvement of the Lys amino group causes that copper binding to PrP 106-111 is much more effective than to the N-protected version of this peptide.

Close to His111 there is a second His residue at position 96. When the PrP 91-105 fragment is added to the neurotoxic PrP 106-126 peptide, the possibility arises of simultaneous binding of His96 and His111 to the same metal ion. However, the fifth Cu2+ ion outside of the octarepeat region was suggested to bind at His96 only [27,34]. The three dimensional likely structure of PrP with five bound metal ions suggested in the latter case is shown in Figure 12. The involvement of both, His96 and His111 in the coordination of one copper ion

Figure 11. NMR structure of the Cu(II) complex of the prion neurotoxic peptide. (Reproduced by permission from [48]).

Figure 12. Model of the three-dimensional structure of PrP 61-231 with coppers included. (Reproduced by permission from [34]).

octarepeat domain

Figure 12. Model of the three-dimensional structure of PrP 61-231 with coppers included. (Reproduced by permission from [34]).

(Figure 13) could create potentially the most powerful metal binding site [49], but really convincing thermodynamic and structural data are still missing. The interaction of copper with the PrP 91-115 fragment is suggested to induce the P-sheet conformation [49]. It has been shown that the neurotoxic peptide region of PrP is vital for PrP propagation and protein aggregation and it could be linked with copper binding [27,28,34,49,50].

The Mn2+ ions seem to have a critical impact on PrP oxidative chemistry [51]. The neurotoxic peptide seems to interact with Mn2+ ions quite efficiently [48]. However, the binding sites are completely different than those of Cu2+ ions. The Mn2+ ions interact with the neurotoxic peptide via the carbonyl oxygen atoms of Gly124 and Lys125 amide bonds and they approach the carboxylate of Gly126. Mn2+ ions also interact, most likely through hydrogen bonding by a metal-coordinated water molecule, with the imidazole ring of His111 [48]. Thus, even if manganese may not be able to substitute copper ions it could affect oxidative activity of metal-bound PrP using the oxygen donor set of the prion protein.

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