The specificity of interaction of Zn²⁺, Ni²⁺ and Cu²⁺ ions with the histidine-rich domain of the TjZNT1 ZIP family transporter

Abstract

The Zrt/Irt-like protein (ZIP) family contributes to the metal homeostasis by regulating the transport of divalent metal cations such as Fe(2+), Zn(2+), Mn(2+), Cd(2+) and sometimes even Cu(2+). Most ZIP members have a long variable loop between transmembrane domains (TMDs) III and IV; this region is predicted to be located in the cytoplasm and is postulated to be the metal ion binding site. In this study, we looked at the thermodynamic behavior and coordination chemistry of Zn(2+), Ni(2+) and Cu(2+) complexes with the histidine-rich domain, Ac-(185)RAHAAHHRHSH(195)-NH2 (HRD), from the yeast TjZNT1 protein, located between TMDs III and IV. The sequence is conserved also in higher species like Thlaspi japonicum. The stability of complexes increases in the series Ni(2+) < Zn(2+)≪ Cu(2+). The geometry of complexes is very different for each metal and in the case of Zn(2+) complexes, high specificity in binding is observed. Moreover, the stability of HRD-Cu(2+) complexes was compared with the five His residues containing peptide from Hpn protein (Helicobacter pylori). The results suggest a high ability of HRD in the binding of all three studied metals.

Functional Regulation of the Plasma Protein Histidine-Rich Glycoprotein by Zn2+ in Settings of Tissue Injury

“…Interestingly, this study described unpublished results suggesting that these immobilized fragments when bound either to Cu 2+ or Zn 2+ , showed altered selectivity patterns in pull - down assays from human plasma [37]. Other reported cases of histidine-rich sequences or flexible loop regions that have been described to interact with divalent metals to regulate a number of functions, include (i) transporter properties by TjZNT1 [38] and ZnuA [39]; (ii) storage capabilities by the cytoplasmic protein Hpn [40]; (iii) initiate catalysis of the superoxide anion into oxygen and hydrogen peroxide by the Cu, Zn superoxide dismutase [41] and (iv) enable the formation of plaque-thread junctions by the Mytilus californianus foot protein 4 (mcfp-4) protein [42]. This proposes that the binding of metals by HRG will be dictated by their distribution in tissues, something that will vary depending on the particular physiological or pathological setting, that in turn will regulate ligand binding and therefore function of HRG.…”

Investigations on Zinc Isotope Fractionation in Breast Cancer Tissue Using in vitro Cell Culture Uptake-Efflux Experiments

“…Histidine-, glutamate-, aspartate- and cysteine-residues serve as binding ligands for Zn in these proteins. In general, histidine-rich loops form the primary Zn-binding sites of ZIPs and ZnTs ( 20 ), while Zn-binding on metallothionein occurs on cysteine-rich ligands ( 21 , 22 ). Cancer-induced Zn dyshomeostasis has been related to up- or down-regulation of Zn proteins ( 23 ) and changes in their coordination and ligand chemistry ( 24 ).…”

Copper Binding Features of Tropomyosin-Receptor-Kinase-A Fragment: Clue for Neurotrophic Factors and Metals Link

“…The UV-vis λ max was similar to that of [CuLH −1 ] + species but the band was narrow, suggesting fewer isomers were present compared to mono complexes analogous. Notably, the EPR parameters were different and indicative of a [3N Im , N − ] coordination environment [46,47]. The CD spectrum carried out at this pH value was similar to that obtained at a 1:1 metal-to-ligand molar ratio.…”