Tau (τ) is a 441-mer peptide present in significant amounts in neurons, where it contributes to the stabilization of microtubules. Insoluble amyloid aggregates of tau are associated with over 20 neurological disorders known as tauopathies, among which is Parkinson’s [1]. In neurons, tau binds tubulin through its microtubule binding domain which comprises four repeats (R1-R4) characterized by the presence of histidine residues. These regions are potential binding sites for metal ions [2]. The elucidation of the binding capacities toward metal ions, especially those redox active such as copper(II), may shed light on the biomolecular processes that underlie the progression of tauopathies [3]. In this contribution we examine the thermodynamic stability of copper(I) and copper(II) adducts with two peptide fragments which are encompassed in the R1 and R3 repeats of tau, namely Ac- 257VKSKIGSTENLKHQGGG273-NH2 (R1τ, HL1 in its neutral form) and Ac-323GSLGNIHHKPGGG335- NH2 (R3τ, L3 in its neutral form). Copper(II) binding to R1τ (HL1) at pH 7.4 is dominated by the formation of [Cu(HL1)]2+, where (L1)- is tridentate. The copper(II) equatorial coordination positions are occupied by the imidazole ring of His269, two amido nitrogens, and a water molecule. As for the R3τ (L3) peptide, at pH 7.4 the two most abundant species are [CuL3]2+ and [Cu(L3H-1)]+ (in a ratio of ca. 1:4, Figure 1, left). While copper(II) coordination mode in [Cu(L3H-1)]+ is similar to that in [Cu(HL1)]2+, that of [CuL3]2+ is different and possibly most interesting. Spectroscopic data suggest that in [CuL3]2+ two imidazole donors and one amido nitrogen are equatorially coordinated to copper(II), plus a water molecule (Figure 1, right). The presence of this tandem HisHis fragment makes this peptide interesting in view of the stabilization of copper(I). Indeed, spectroscopic competition titration using a metallochromic indicator clearly showed that copper(I) binds significantly to R3τ at neutral pH but not to R1τ. The catalytic activity in reactions of oxidation of catecholes and the NMR features of these complexes will be discussed in terms of the speciation of the thermodynamic stability of these complexes with copper in both oxidation states. The authors acknowledge MIUR for financial support through the project "Metal ions, dopamine, and oxidative stress in Parkinson's disease” (PRIN 2015T778JW). References [1] M. Goedert, D. S. Eisenberg, R. A. Crowther, Annu. Rev. Neurosci. 40 (2017) 189–210. J.A. White "Biological inorganic chemistry" (1973) Oxford University Press, Oxford. [2] M. G. Savelieff, S. Lee, Y. Liu, M. H. Lim, ACS Chem. Biol. 8 (2013) 856–865. [3] A. Soragni, B. Zambelli, M. D. Mukrasch, J. Biernat, S. Jeganathan, C. Griesinger, S. Ciurli, E. Mandelkow, M. Zweckstetter, Biochemistry 47 (2008) 10841–10851.
Copper(I) and Copper(II) Binding to R1 and R3 Fragments of Tau Protein
Denise Bellotti;Maurizio Remelli;
2019
Abstract
Tau (τ) is a 441-mer peptide present in significant amounts in neurons, where it contributes to the stabilization of microtubules. Insoluble amyloid aggregates of tau are associated with over 20 neurological disorders known as tauopathies, among which is Parkinson’s [1]. In neurons, tau binds tubulin through its microtubule binding domain which comprises four repeats (R1-R4) characterized by the presence of histidine residues. These regions are potential binding sites for metal ions [2]. The elucidation of the binding capacities toward metal ions, especially those redox active such as copper(II), may shed light on the biomolecular processes that underlie the progression of tauopathies [3]. In this contribution we examine the thermodynamic stability of copper(I) and copper(II) adducts with two peptide fragments which are encompassed in the R1 and R3 repeats of tau, namely Ac- 257VKSKIGSTENLKHQGGG273-NH2 (R1τ, HL1 in its neutral form) and Ac-323GSLGNIHHKPGGG335- NH2 (R3τ, L3 in its neutral form). Copper(II) binding to R1τ (HL1) at pH 7.4 is dominated by the formation of [Cu(HL1)]2+, where (L1)- is tridentate. The copper(II) equatorial coordination positions are occupied by the imidazole ring of His269, two amido nitrogens, and a water molecule. As for the R3τ (L3) peptide, at pH 7.4 the two most abundant species are [CuL3]2+ and [Cu(L3H-1)]+ (in a ratio of ca. 1:4, Figure 1, left). While copper(II) coordination mode in [Cu(L3H-1)]+ is similar to that in [Cu(HL1)]2+, that of [CuL3]2+ is different and possibly most interesting. Spectroscopic data suggest that in [CuL3]2+ two imidazole donors and one amido nitrogen are equatorially coordinated to copper(II), plus a water molecule (Figure 1, right). The presence of this tandem HisHis fragment makes this peptide interesting in view of the stabilization of copper(I). Indeed, spectroscopic competition titration using a metallochromic indicator clearly showed that copper(I) binds significantly to R3τ at neutral pH but not to R1τ. The catalytic activity in reactions of oxidation of catecholes and the NMR features of these complexes will be discussed in terms of the speciation of the thermodynamic stability of these complexes with copper in both oxidation states. The authors acknowledge MIUR for financial support through the project "Metal ions, dopamine, and oxidative stress in Parkinson's disease” (PRIN 2015T778JW). References [1] M. Goedert, D. S. Eisenberg, R. A. Crowther, Annu. Rev. Neurosci. 40 (2017) 189–210. J.A. White "Biological inorganic chemistry" (1973) Oxford University Press, Oxford. [2] M. G. Savelieff, S. Lee, Y. Liu, M. H. Lim, ACS Chem. Biol. 8 (2013) 856–865. [3] A. Soragni, B. Zambelli, M. D. Mukrasch, J. Biernat, S. Jeganathan, C. Griesinger, S. Ciurli, E. Mandelkow, M. Zweckstetter, Biochemistry 47 (2008) 10841–10851.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
