Metallothioneins

Abstract

Metallothioneins (MTs) are small cysteine-rich proteins that bind multiple metal ions in characteristic metal-thiolate clusters. They have been identified and studied in both prokaryotes, where they seem to be limited to a relatively small number of genera, and eukaryotes, where they are nearly ubiquitous. These are the archetypal cytosolic binders and transporters of essential and non-essential d10 metal ions, in particular Zn(II), Cu(I) and Cd(II). The term “metallothioneins” encompasses proteins that are not related through recognizable sequence similarity or even fold similarity, but through an extraordinarily high abundance of cysteine residues, and their metal ion binding ability. Considering the diversity of their primary structures, there is a high likelihood for “metallothioneins” having evolved more than once, i.e. they are thought to constitute a polyphyletic group of proteins. Their structural diversity is accompanied by functional versatility; physiological functions are diverse and include detoxifying and/or trafficking both essential and non-essential metal ions, regulating intracellular availability of Zn or Cu and providing an easily mobilized storage facility for Zn or Cu, depending on the organism concerned. They also can be cellular antioxidants and may link the cellular redox state and Zn status. Depending on organism and tissue, different MTs may have different functions, and even a single MT may perform several of these roles. Indeed, the regulatory DNA sequences of some mammalian MTs harbour not only metal-responsive elements (MREs), but also elements that respond to glucocorticoids (GREs) and oxidative stress (AREs), amongst many other cis-acting elements. This chapter will focus on the structures and in vitro chemistry of metallothioneins from both eukaryotes (including those from vertebrates, invertebrates, plants and fungi) and prokaryotes (including those from cyanobacteria and mycobacteria). The polyphyletic origins of MTs and the resulting diversity of MTs from different phyla in terms of biophysical properties and biological functions emphasize the ongoing need for in-depth studies. It is inappropriate to extrapolate properties and functions from one MT to another.