OK folks, so you thought you'd got your head around thyroid hormones. You really have done a lot of reading. You recognise all the abbreviations and technical terms. You think it all hangs together.
Then someone throws in another idea - one that potentially adds another order of magnitude of complexity...
I can't tell you what I'll say if a doctor ever tries to tell me that hypothyroidism is simple...
Curr Top Dev Biol. 2017;125:1-38. doi: 10.1016/bs.ctdb.2017.02.003. Epub 2017 Mar 25.
Evolution of Nuclear Receptors and Ligand Signaling: Toward a Soft Key-Lock Model?
Holzer G1, Markov GV2, Laudet V3
1 Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, Ecole Normale Supérieure de Lyon, Lyon Cedex 07, France.
2 Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR 8227, Integrative Biology of Marine Models, Station Biologique de Roscoff, Place Georges Teissier, Roscoff Cedex, France.
3 Observatoire Océanologique de Banyuls-sur-Mer, UMR7232, Université Pierre et Marie Curie, Paris, Banyuls-sur-Mer, France. Electronic address: firstname.lastname@example.org.
Nuclear receptors (NRs) are a family of ligand-regulated transcription factors that modulate a wide variety of physiological functions in a ligand-dependent manner. The first NRs were discovered as receptors of well-known hormones such as 17β-estradiol, corticosteroids, or thyroid hormones. In these cases a direct activation of the receptor transcriptional activity by a very specific ligand, with nanomolar affinity, was demonstrated, providing a strong conceptual framework to understand the mechanism of action of these hormones. However, the discovery that some NRs are able to bind different ligands with micromolar affinity was a first sign that the univocal relationship between a specific receptor (e.g., TR) and a specific ligand (e.g., thyroid hormone) should not be generalized to the whole family. These discussions about the nature of NR ligands have been reinforced by the study of the hormone/receptor couple evolution. Indeed when the ligand is not a protein but a small molecule derived from a biochemical pathway, a simple coevolution mechanism between the ligand and the receptor cannot operate. We and others have recently shown that the ligands acting for a given NR early on during evolution were often different from the classical mammalian ligands. This suggests that the NR/ligand evolutionary relationship is more dynamic than anticipated and that the univocal relationship between a receptor and a specific molecule may be an oversimplification. Moreover, classical NRs can have different ligands acting in a tissue-specific fashion with significant impact on their function. This also suggests that we may have to reevaluate the pharmacology of the ligand/receptor couple.
© 2017 Elsevier Inc. All rights reserved.
Alternative ligands; Evolution; Ligand; Nuclear receptors; Pharmacology; Phylogeny; Retinoic acid; Steroids; Thyroid hormones