The Functions of Metamorphic Metallothioneins in Zinc and Copper Metabolism

Abstract

Recent discoveries in zinc biology provide a new platform for discussing the primary physiological functions of mammalian metallothioneins (MTs) and their exquisite zinc-dependent regulation. It is now understood that the control of cellular zinc homeostasis includes buffering of Zn2+ ions at picomolar concentrations, extensive subcellular re-distribution of Zn2+, the loading of exocytotic vesicles with zinc species, and the control of Zn2+ ion signalling. In parallel, characteristic features of human MTs became known: their graded affinities for Zn2+ and the redox activity of their thiolate coordination environments. Unlike the single species that structural models of mammalian MTs describe with a set of seven divalent or eight to twelve monovalent metal ions, MTs are metamorphic. In vivo, they exist as many species differing in redox state and load with different metal ions. The functions of mammalian MTs should no longer be considered elusive or enigmatic because it is now evident that the reactivity and coordination dynamics of MTs with Zn2+ and Cu+ match the biological requirements for controlling—binding and delivering—these cellular metal ions, thus completing a 60-year search for their functions. MT represents a unique biological principle for buffering the most competitive essential metal ions Zn2+ and Cu+. How this knowledge translates to the function of other families of MTs awaits further insights into the specifics of how their properties relate to zinc and copper metabolism in other organisms.

Crosstalk of the structural and zinc buffering properties of mammalian metallothionein-2

“…However, it is now well known that metallothioneins are Zn(II) and Cu(I) metalloproteins in healthy living organisms. [72][73][74][75][76] Comparison of NMR data obtained for zinc and cadmium metallothioneins in the early 1990s shows that both molecules are structurally similar in terms of cluster geometry, metal-sulfur bonds and overall shape, although some differences in intraprotein connectivities and protein volume were detected. 77,78 Differences between these metal ions include (i) their ionic radii (109 pm for Cd(II) and 88 pm for Zn(II)), (ii) hard and soft acid-base properties -Cd(II) is a soft Lewis acid while Zn(II) is considered borderline, 79 and (iii)…”

“…80,81 To date, there are a limited number of reports focusing on the biophysical properties of zinc metallothioneins, although it is the most abundant MT form in mammals. 76 Various physicochemical studies including CD, MCD, UV-Vis, and NMR spectroscopy on mammalian metallothioneins show that Cd(II) binds more tightly than Zn(II) ions, which is well understood when considering the enthalpy of M-S bond formation and highly similar structure. The results presented in this article support a model with varied Zn(II) affinities towards MT2.…”

“…11 Therefore the understanding of this process is not only important for exploration of the structural nature of this enigmatic protein, but also critical for understanding the principles of other metallothionein functions, which we are still trying to understand 60 years after its discovery. 76 …”

The Coordination Chemistry of Copper Uptake and Storage for Methane Oxidation

“…The ability of the relatively small Cys‐rich metallothioneins (MTs) to bind and store Cu I in eukaryotes is well established . A homologue (MymT) has been identified in pathogenic mycobacteria that provided, prior to the discovery of the Csps, a very rare example of Cu storage in bacteria.…”

“…A homologue (MymT) has been identified in pathogenic mycobacteria that provided, prior to the discovery of the Csps, a very rare example of Cu storage in bacteria. Eukaryotic MTs are also able to store Zn II , and can bind other metals with a d 10 electronic configuration, including the highly toxic Cd II and Hg II . Due to difficulties in obtaining suitable crystals, NMR has been extensively used to study solution structures of Cu I ‐MTs, but provides limited information about the Cu I sites .…”