Induction, regulation, degradation, and biological significance of mammalian metallothioneins

MTs are small cysteine-rich metal-binding proteins found in many species an d, although there are differences between them, it is of note that they hav e a great deal of sequence and structural homology. Mammalian MTs are 61 or 62 amino acid polypeptides containing 20 conserved cysteine residues that underpin the binding of metals. The existence of MT across species is indic ative of its biological demand, while the conservation of cysteines indicat es that these are undoubtedly central to the function of this protein. Four MT isoforms have been found so far, MT-1, MT-2, MT-3, and MT-4, but these also have subtypes with 17 MT genes identified in man, of which 10 are know n to be functional. Different cells express different MT isoforms with vary ing levels of expression perhaps as a result of the different function of e ach isoform. Even different metals induce and bind to MTs to different exte nts. Over 40 years of research into MT have yielded much information on thi s protein, but have failed to assign to it a definitive biological role. Th e fact that multiple MT isoforms exist, and the great variety of substances and agents that act as inducers, further complicates the search for the bi ological role of MTs. This article reviews the current knowledge on the bio chemistry, induction, regulation, and degradation of this protein in mammal s, with a particular emphasis on human MTs. It also considers the possible biological roles of this protein, which include participation in cell proli feration and apoptosis, homeostasis of essential metals, cellular free radi cal scavenging, and metal detoxification.