Different Behavior of the Histidine Residue toward Cadmium and Zinc in a Cadmium-Specific Metallothionein from an Aquatic Fungus

Abstract

Metallothioneins (MTs) are a large superfamily of ubiquitous cysteine-rich metalloproteins with main functions in metal ion homeostasis and detoxification. Neclu_MT1 is a metallothionein from the aquatic fungus Heliscus lugdunensis and so far the only known MT that is solely induced by CdII but not by ZnII or copper ions. In addition to eight cysteine residues, Neclu_MT1 also contains a less common single C-terminal histidine residue. To better understand the role of this histidine residue in metal ion binding, for the first time, potentiometric pH titrations are applied, revealing insights into the protonation and metal ion binding processes. Additional studies with absorption and NMR spectroscopy complement the finding that while the histidine residue is not crucial for the overall metal binding capacity, it does serve as a ligand in the ZnII but not in the CdII form of the protein.

Aggregation behavior of group 12 complexes of a tripodal mixed NS(thiolato) donor ligand

“…2 Evidence for histidine metal bonding has also recently been reported for several cysteine-rich metallothioneins, proteins with functions including zinc homeostasis as well as Cd 2+ and Hg 2+ detoxification. 3 Human proteins containing zinc centers with both histidine and cysteine side chain ligation occur in the catalytic sites of at least four enzyme classes (Table 1). Structural and regulatory Zn-Cys-His sites occur in at least five classes of mammalian enzymes (Table 2).…”

Homo- and Heteronuclear Group 12 Metallothionein Type B Cluster Analogs: Synthesis, Structure, 1H NMR and ESI-MS

“…26,27,36 Interestingly, although the aromatic nitrogen-containing amino acid histidine is absent from the isoforms of human MT, it occurs frequently in the MTs from other species. 37,38 Furthermore, there is evidence from NMR, 10 EXAFS, 39 and histidine modification analyses 40 for histidine ligation of the MT metal clusters in plants and microorganisms. We took inspiration from these studies to further investigate pyridyl groups as potential synthons for nonproteinaceous metallothionein-like aggregates with monocyclic M 3 S 3 cores.…”

“…Significantly, ions matching the predicted isotope patterns for clusters with Hg 3 S 3 and Hg 4 S 5 cores were both observed in ESI-MS characterization of an acetonitrile solution of this cluster. The three structurally characterized metallothionein-like thiolate-bridged group 12 metal ion clusters have mixed aromatic amine, monothiolato (N x A S – ) ligands in common. ,, Interestingly, although the aromatic nitrogen-containing amino acid histidine is absent from the isoforms of human MT, it occurs frequently in the MTs from other species. , Furthermore, there is evidence from NMR, EXAFS, and histidine modification analyses for histidine ligation of the MT metal clusters in plants and microorganisms. We took inspiration from these studies to further investigate pyridyl groups as potential synthons for nonproteinaceous metallothionein-like aggregates with monocyclic M 3 S 3 cores.…”

Cadmium Exchange with Zinc in the Non-Classical Zinc Finger Protein Tristetraprolin

“…43,44 There is published evidence for Cd binding to cysteine-rich proteins, including studies with several types of ZFs (e.g., TFIIIA, SP1, and XPA), as well as metallothioneins. [44][45][46][47][48][49][50][51][52][53][54][55][56] Cd is known to have proinflammatory effects triggering inflammatory response and there is evidence that TTP levels are increased upon Cd exposure, suggesting that TTP may be a target of Cd toxicity. [57][58][59][60] Our laboratory has previously investigated direct binding of Cd to a functional construct of TTP that contains the two CCCH ZF domains (TTP-2D).…”

“…One potential factor that may promote misregulation of TTP is cadmium (Cd). Cd is a known environmental carcinogen, with major sources of exposure including waste from the industrial production of batteries and plastics, car exhaust, and cigarette smoke. − The biological targets of Cd are not clear; however, cysteine rich proteins are potential targets because cadmium a “soft acid” and cysteine thiolates are a “soft bases.” , There is published evidence for Cd binding to cysteine-rich proteins, including studies with several types of ZFs (e.g., TFIIIA, SP1, and XPA), as well as metallothioneins. − Cd is known to have proinflammatory effects triggering inflammatory response and there is evidence that TTP levels are increased upon Cd exposure, suggesting that TTP may be a target of Cd toxicity. − …”