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Cross‐Talk Between the Octarepeat Domain and the Fifth Binding Site of Prion Protein Driven by the Interaction of Copper(II) with the N‐terminus
Author(s) -
Di Natale Giuseppe,
Turi Ildikó,
Pappalardo Giuseppe,
Sóvágó Imre,
Rizzarelli Enrico
Publication year - 2015
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201405502
Subject(s) - peptide , chemistry , circular dichroism , potentiometric titration , copper , amide , crystallography , metal , biophysics , scrapie , stereochemistry , prion protein , biochemistry , ion , organic chemistry , biology , medicine , disease , pathology
Prion diseases are a group of neurodegenerative diseases based on the conformational conversion of the normal form of the prion protein (PrP C ) to the disease‐related scrapie isoform (PrP Sc ). Copper(II) coordination to PrP C has attracted considerable interest for almost 20 years, mainly due to the possibility that such an interaction would be an important event for the physiological function of PrP C . In this work, we report the copper(II) coordination features of the peptide fragment Ac(PEG 11 ) 3 PrP(60‐114) [Ac=acetyl] as a model for the whole N‐terminus of the PrP C metal‐binding domain. We studied the complexation properties of the peptide by means of potentiometric, UV/Vis, circular dichroism and electrospray ionisation mass spectrometry techniques. The results revealed that the preferred histidyl binding sites largely depend on the pH and copper(II)/peptide ratio. Formation of macrochelate species occurs up to a 2:1 metal/peptide ratio in the physiological pH range and simultaneously involves the histidyl residues present both inside and outside the octarepeat domain. However, at increased copper(II)/peptide ratios amide‐bound species form, especially within the octarepeat domain. On the contrary, at basic pH the amide‐bound species predominate at any copper/peptide ratio and are formed preferably with the binding sites of His96 and His111, which is similar to the metal‐binding‐affinity order observed in our previous studies.