Evolution of the Thyroid Hormone-Binding Protein, Transthyretin

Abstract

Transthyretin (TTR) belongs to a group of proteins, which includes thyroxine-binding globulin and albumin, that bind to and transport thyroid hormones in the blood. TTR is also indirectly implicated in the carriage of vitamin A through the mediation of retinol-binding protein (RBP). It was first identified in 1942 in human serum and cerebrospinal fluid and was formerly called prealbumin for its ability to migrate faster than serum albumin on electrophoresis of whole plasma. It is a single polypeptide chain of 127 amino acids (14,000 Da) and is present in the plasma as a tetramer of noncovalently bound monomers. The major sites of synthesis of TTR in eutherian mammals, marsupials, and birds are the liver and choroid plexus but in reptiles it is synthesised only in the choroid plexus. The observation that TTR is strongly expressed in the choroid plexus but not in the liver of the stumpy-tailed lizard and the strong conservation of expression in the choroid plexus from reptiles to mammals have been taken as evidence to suggest that extrahepatic synthesis of TTR evolved first. The identification and cloning of TTR from the liver of an amphibian, Rana catesbeiana, and a teleost fish, Sparus aurata, and its absence from the choroid plexus of both species suggest an alternative model for its evolution. Protein modelling studies are presented that demonstrate differences in the electrostatic characteristics of the molecule in human, rat, chicken, and fish, which may explain why, in contrast to TTR from human and rat, TTR from fish and birds preferentially binds triiodo-L-thyronine.

Exposure to DE-71 alters thyroid hormone levels and gene transcription in the hypothalamic–pituitary–thyroid axis of zebrafish larvae

“…It has been proposed that TTR is a key TH carrier protein that maintains extrathyroidal stores of the hormone, regulates the supply of the hormone to various target tissues, and plays an important role in the thyroid axis in fish (Power et al, 2000;Kawakami et al, 2006). In addition, albumin and thyroxine-binding globulin (TBG) are also binding to THs in fish plasma (Lema et al, 2008).…”

Hormone affinity and fibril formation of piscine transthyretin: The role of the N-terminal

“…However, sequence identity of TTR from the former species and amphibian and fish is considerably lower (from 48 to 55% in fish or 62% in amphibian) (Power et al, 2000).…”

“…Despite conservation of TTR structure between sea bream and other vertebrates, the surface potential, most noticeably in the thyroid hormone-binding site is more negative in the sea bream and the N-terminus of the protein is longer (Power et al, 2000).…”

“…Moreover, comparative studies of three-dimensional structure models of human, rat, chicken and sea bream TTR, revealed a highly conserved tetrameric structure but a surface potential, especially at the TH binding site, more negative (close to -15 kT/e) in chicken and sea bream than human and rat (close to 0 kT/e) (Power et al, 2000).…”

“…For example, TTR is present principally in the liver and to a lesser extent in the brain and other tissue of teleost fish (Power et al, 2000, Santos and Power, 1996, Santos and Power, 1999 but in turtles (Trachemys scripta) it is expressed principally in the choroid plexus . Moreover, some metatherian (marsupial) species contain TTR in the blood stream, whereas other do not (Richardson et al, 1994).…”