Mn(II) and Zn(II) interactions with peptide fragments from Parkinson's disease genes

Two peptide sequences from PARK9 Parkinson's disease gene, ProAspGluLysHisGluLeu, (P 1D 2E 3K 4H 5E 6L 7) (1) and PheCysGlyAspGlyAlaAsnAspCysGly (F 1C 2G 3D 4G 5A 6N 7D 8C 9G 10) (2) were tested for Mn(ii), Zn(ii) and Ca(ii) binding. The fragments are located from residues 1165 to 1171 and 1184 to 1193 in the PARK9 encoded protein. This protein can protect cells from poisoning of manganese, which is an environmental risk factor for a Parkinson's disease-like syndrome. Mono- and bi-dimensional NMR spectroscopy has been used to understand the details of metal binding sites at different pH values and at different ligand to metal molar ratios. Mn(ii) and Zn(ii) coordination with peptide (1) involves imidazole N ε or N δ of His 5 and carboxyl γ-O of Asp 2, Glu 3 and Glu 6 residues. Six donor atoms participate in Mn(ii) binding resulting in a distorted octahedral geometry, possibly involving bidentate interaction of carboxyl groups; four donor atoms participate in Zn(ii) binding resulting in a tetracoordinate geometry. Mn(ii) and Zn(ii) coordination involves the two cysteine residues with peptide (2); Mn(ii) accepts additional ligand bonds from the carboxyl γ-O of Asp 4 and Asp 8 to complete the coordination sphere; the unoccupied sites may contain solvent molecules. The failure of Ca(ii) ions to bind to either peptide (1) or (2) appears to result, under our conditions, from the absence of chelating properties in the chosen fragments.