Molecular and thyroid hormone binding properties of lamprey transthyretins: The role of an N-terminal histidine-rich segment in hormone binding with high affinity

Kasai, Kentaro; Nishiyama, Norihito; Yamauchi, Kiyoshi

doi:10.1016/j.mce.2018.02.012

Cited by 7 publications

(1 citation statement)

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“…Albumin and TBG have higher affinity for T4 than for T3 in all species studied. However, this is not the case for TTR: in all studied species of birds, reptiles, amphibians, and fish [with the notable exception of sea bream, where TTR had similar affinity for T3 and T4 (18)],TTR has higher affinity for T3 than for T4 (19–24). Only in mammals, does TTR have higher affinity for T4 than for T3 [for a detailed discussion on how and why this may have occurred during evolution, see (25)].…”

Section: Thyroid Hormone Distributor Proteins (Thdps)mentioning

confidence: 98%

Thyroid Hormone Distributor Proteins During Development in Vertebrates

et al. 2019

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Thyroid hormones (THs) are ancient hormones that not only influence the growth, development and metabolism of vertebrates but also affect the metabolism of (at least some) bacteria. Synthesized in the thyroid gland (or follicular cells in fish not having a discrete thyroid gland), THs can act on target cells by genomic or non-genomic mechanisms. Either way, THs need to get from their site of synthesis to their target cells throughout the body. Despite being amphipathic in structure, THs are lipophilic and hence do not freely diffuse in the aqueous environments of blood or cerebrospinal fluid (in contrast to hydrophilic hormones). TH Distributor Proteins (THDPs) have evolved to enable the efficient distribution of THs in the blood and cerebrospinal fluid. In humans, the THDPs are albumin, transthyretin (TTR), and thyroxine-binding globulin (TBG). These three proteins have distinct patterns of regulation in both ontogeny and phylogeny. During development, an additional THDP with higher affinity than those in the adult, is present during the stage of peak TH concentrations in blood. Although TTR is the only THDP synthesized in the central nervous system (CNS), all THDPs from blood are present in the CSF (for each species). However, the ratio of albumin to TTR differs in the CSF compared to the blood. Humans lacking albumin or TBG have been reported and can be asymptomatic, however a human lacking TTR has not been documented. Conversely, there are many diseases either caused by TTR or that have altered levels of TTR in the blood or CSF associated with them. The first world-wide RNAi therapy has just been approved for TTR amyloidosis.

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Section: Thyroid Hormone Distributor Proteins (Thdps)mentioning

confidence: 98%

Thyroid Hormone Distributor Proteins During Development in Vertebrates

et al. 2019

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Sequential Molecular Events of Functional Trade-Offs in 5-Hydroxyisourate Hydrolase Before and After Gene Duplication Led to the Evolution of Transthyretin During Chordate Diversification

Yamauchi

Kasai

2018

J Mol Evol

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Transthyretin (TTR), a plasma thyroid hormone distributor protein (THDP), emerged from 5-hydroxyisourate hydrolase (HIUHase), an enzyme involved in urate metabolism, by gene duplication at a stage of chordate evolution. Comparison of amino acid sequences revealed the presence of two His-rich segments in the primitive TTRs. Using several HIUHase and TTR mutants, we investigated 5-hydroxyisourate (HIU) hydrolysis activity and thyroid hormone (TH) binding activity to elucidate how a novel function as a THDP arose. Lancelet HIUHase was found to have higher enzyme activity than trout HIUHase. Two amino acid substitutions, R54E/Y119T, at the active sites of HIUHase, exerted weak [I]-3,3',5-triiodo-L-thyronine ([I]T3) binding activity with a concomitant loss of HIU hydrolysis activity. Addition of 3×His (3×H) to the N-terminal end weakened HIU hydrolysis activity of both lancelet and trout HIUHases, whereas it enhanced T3-binding activity of HIUHase R54E/Y119T. Trout HIUHase 3×H R54E/Y119T had higher [I]T3-binding activity than that of lancelet HIUHase 3×H R54E/Y119T, with a K of 143 nM, and displayed metal dependency and no TH binding specificity. Deletion of the N-terminal His-rich segment from lamprey TTR decreased T3-binding activity, while addition of 3×H to trout TTR increased T3-binding activity, while maintaining TH binding specificity. Our results suggest that functional trade-offs of HIU hydrolysis activity with TH binding activity might have sequentially occurred before and after gene duplication, and that TH binding specificity and high-affinity sites may have been acquired later in the course of TTR evolution.

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