Metallothioneins with unusual residues: histidines as modulators of zinc affinity and reactivity

For many years, paradigms regarding metallothioneins comprised the exclusive metal coordination by thiolates from cysteine residues and the absence of aromatic residues. As more sequence and in vitro data on metallothioneins, in particular from non-vertebrate organisms, has become available, both the occurrence of and metal coordination by histidine residues in metallothioneins is emerging as a more frequent feature than expected. We discuss the general implications of histidines versus cysteines in zinc binding sites, and review some recent results from literature and our own lab. We conclude that histidines can stabilise metallothionein clusters by reducing the overall charge, offering the ability to help with structural organisation by supplying H-bond donor and acceptor properties, reducing the likelihood for disulfide bond formation, whilst maintaining a high affinity towards metal ions, in particular the borderline zinc ion.