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. 2014 Jan 29;281(1779):20132747.
doi: 10.1098/rspb.2013.2747. Print 2014 Mar 22.

Temperature-responsive release of thyroxine and its environmental adaptation in Australians

Xiaoqiang Qi  1 , Wee Lee Chan, Randy J Read, Aiwu Zhou, Robin W Carrell
Affiliations

Temperature-responsive release of thyroxine and its environmental adaptation in Australians

Xiaoqiang Qi et al. Proc Biol Sci. .

Abstract

The hormone thyroxine that regulates mammalian metabolism is carried and stored in the blood by thyroxine-binding globulin (TBG). We demonstrate here that the release of thyroxine from TBG occurs by a temperature-sensitive mechanism and show how this will provide a homoeostatic adjustment of the concentration of thyroxine to match metabolic needs, as with the hypothermia and torpor of small animals. In humans, a rise in temperature, as in infections, will trigger an accelerated release of thyroxine, resulting in a predictable 23% increase in the concentration of free thyroxine at 39°C. The in vivo relevance of this fever-response is affirmed in an environmental adaptation in aboriginal Australians. We show how two mutations incorporated in their TBG interact in a way that will halve the surge in thyroxine release, and hence the boost in metabolic rate that would otherwise occur as body temperatures exceed 37°C. The overall findings open insights into physiological changes that accompany variations in body temperature, as notably in fevers.

Keywords: aboriginal Australian; febrile convulsions; hibernation; hypothermia; thyroxine; thyroxine-binding globulin.

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Figures

Figure 1.
Figure 1.
Temperature-responsive release of thyroxine from TBG. (a) Thyroxine, in space-filling form. Movement of the reactive centre loop (yellow) into and out of the A-sheet (red) of TBG directly affects the binding site magnified in (b) showing the interactions that stabilize thyroxine (skeletal form) in the binding site. Entry of the reactive centre loop will cause a steric perturbation and the expansion of the A-sheet will displace the connecting loops (green) that surround the bound thyroxine. The Australian mutations, A191T and L283F, flank the binding site. (c,d) The proportional loss of hormone-binding affinity with increasing temperature (Kd/Kd37°C): (c) shown with the homologous CBG, from Chan [7] circles and Mickelson [14] crosses; (d) with TBG and fluorophore–thyroxine data from table 1. The plot of the L283F variant of TBG (interrupted line) is superimposable on that of the wild-type, including the inflection at 37°C.
Figure 2.
Figure 2.
Variation in free thyroxine with temperature from Kd/Kd37°C ratios (hatched bars), 20 pM at 37°C rising to 25 pM at 39°C with wt-TBG, but dampened to 22 pM in the 191/283 TBG (Aus) variant (upper normal limit, dashed line). The open (non-hatched) bars show values from independent determinations by others using plasma-derived thyroxine [18] and direct assays of plasma-free thyroxine [19,20]. The comparative bars are based on a defined Kd of 80 pM, free thyroxine of 20 pM and a TBG saturation of 20%, at 37°C.
Figure 3.
Figure 3.
Changed binding affinity of Australian variant TBG at raised body temperatures. (a) Modified response of the A191T variant (full line) and the double A191T/L283F variant (red) compared with wild-type TBG (interrupted line). (b) Percentage increase in free thyroxine (ΔFT4) at 39°C and percent-saturation of each variant needed to give a free thyroxine of 20 pM at 37°C, calculated from Kd39°C/Kd37°C ratio and derived thyroxine affinity (T4-Kd37°C) from table 1a. (c). As with the plasma variant [27,28], the recombinant A191/L283F TBG (black) has a small diminution in thermal stability to 52°C, compared with the wild-type 55°C [9]. The identical change in the single A191 recombinant (grey) confirms that the instability is independent of the L283F mutation.
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References

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