The interaction of zinc with the multi-functional plasma thyroid hormone distributor protein, transthyretin: evolutionary and cross-species comparative aspects

A considerable body of evidence has been accumulated showing the interrelationship between zinc and the plasma thyroid hormone (TH) distributor protein, transthyretin (TTR). TTR is a multi-functional protein, which emerged from 5-hydroxyisourate hydrolase (HIUHase) by neo-functionalization after gene duplication during early chordate evolution. HIUHase is also a zinc-binding protein. Most biochemical and molecular biological findings have been obtained from mammalian studies. However, in the past two decades, it has become clear that fish TTR displays zinc-dependent TH binding. After a brief introduction on plasma zinc, THs and their binding proteins, this review will focus on the role of zinc in TTR functions of various vertebrates. In particular primitive fish TTR has an extremely high zinc content, with an increased number of histidine residues which are involved in TH binding. However, zinc-dependent TH binding may have been gradually lost from TTRs during higher vertebrate evolution. Although human TTR has a low zinc content, zinc plays an essential role in TTR functions other than TH binding: the stability of TTR-holo retinol binding protein 4 (holoRBP4) complex, TTR amyloidogenesis, the sequestration of amyloid β (Aβ) fibrils and cryptic proteolytic activity. The interaction of TTR with metallothioneins may be a critical step in the exertion of some of these functions. Evolutionary and physiological insights on zinc-dependent functions of TTRs are also discussed.