Human Prion Protein (hPrPC) is able to bind up to six Cu2+ ions. Four of them can be allocated in the ‘‘octarepeat domain’’, a region of the unstructured N-terminal domain containing four tandem-repetitions of the sequence PHGGGWGQ. It is widely accepted that the additional binding sites correspond to His-96 and His-111 residues. However, recent literature does not agree on the role and the behavior of these sites in Cu2+ complexation to hPrPC. In order to shed more light on this topic, some peptidic analogues of the PrP92–113 fragment were synthesized: (H96A)PrP92–113, (H111A)PrP92–113, (H96Nt-Me-His)PrP92–113, (H111Nt-Me-His)PrP92–113, (H96Nt-Me-His)PrP92–100, (H111Nt-Me-His)PrP106–113, where an alanine or a histidine methylated at the t nitrogen atom of its imidazole ring have been substituted to His-96 or His-111. The first two ligands allowed to confirm that His-111 binding site is stronger than His-96 one: they act as independent sites even at Cu2+ ion substoichiometric levels. Neither multihistidine binding nor bis-complex formation has been detected at neutral pH. Nt methylation gave evidence that t nitrogens of imidazole residues can participate in complex-formation only at acidic pH, where displacement of amidic protons by Cu2+ ions is not allowed. Finally, the length of the fragment does not appear to have any significant influence on the behavior of the two His-96 and His-111 binding sites, from the point of view of either the coordination geometry or their relative strength.

M., R., Valensin, D., D., B., E., G., R., G., Migliorini, C., et al. (2009). The complex-formation behaviour of His residues in the fifth Cu2+ binding site of human Prion protein: a close look. NEW JOURNAL OF CHEMISTRY, 3, 2300-2310 [10.1039/b9nj00202b].

The complex-formation behaviour of His residues in the fifth Cu2+ binding site of human Prion protein: a close look

VALENSIN, DANIELA;MIGLIORINI, CATERINA;
2009

Abstract

Human Prion Protein (hPrPC) is able to bind up to six Cu2+ ions. Four of them can be allocated in the ‘‘octarepeat domain’’, a region of the unstructured N-terminal domain containing four tandem-repetitions of the sequence PHGGGWGQ. It is widely accepted that the additional binding sites correspond to His-96 and His-111 residues. However, recent literature does not agree on the role and the behavior of these sites in Cu2+ complexation to hPrPC. In order to shed more light on this topic, some peptidic analogues of the PrP92–113 fragment were synthesized: (H96A)PrP92–113, (H111A)PrP92–113, (H96Nt-Me-His)PrP92–113, (H111Nt-Me-His)PrP92–113, (H96Nt-Me-His)PrP92–100, (H111Nt-Me-His)PrP106–113, where an alanine or a histidine methylated at the t nitrogen atom of its imidazole ring have been substituted to His-96 or His-111. The first two ligands allowed to confirm that His-111 binding site is stronger than His-96 one: they act as independent sites even at Cu2+ ion substoichiometric levels. Neither multihistidine binding nor bis-complex formation has been detected at neutral pH. Nt methylation gave evidence that t nitrogens of imidazole residues can participate in complex-formation only at acidic pH, where displacement of amidic protons by Cu2+ ions is not allowed. Finally, the length of the fragment does not appear to have any significant influence on the behavior of the two His-96 and His-111 binding sites, from the point of view of either the coordination geometry or their relative strength.
M., R., Valensin, D., D., B., E., G., R., G., Migliorini, C., et al. (2009). The complex-formation behaviour of His residues in the fifth Cu2+ binding site of human Prion protein: a close look. NEW JOURNAL OF CHEMISTRY, 3, 2300-2310 [10.1039/b9nj00202b].
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11365/24150
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