We humans need to classify nature. In many cases, it is a necessary step towards the comprehension of the phenomenon under study. We classify animals, proteins, plants, rocks, clouds… The criteria used to arrange them largely determine their subsequent study.
¿How can we classify nuclear receptors? We can choose between different criteria.
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Genealogical Classification
In this case, they are classified according to a comparison of their sequences. The most similar sequences are grouped in the same set. This similarity between sequences also indicates an evolutionary history. In other words, each subfamily includes “brothers” that would be “cousins” to the members of the other subfamilies.
This classification was recommended by the Nuclear Receptors Nomenclature Committee in 1999. The committee establishes this classification as the base for a new unified nomenclature for the members of this superfamily.
According to this classification, nuclear receptors are grouped in seven subfamilies: NR1, NR2, NR3, NR4, NR5, NR6, and NR0. An interesting fact: this classification matches the DNA-binding characteristics of the members of each subfamily, but not their ligand binding characteristics.
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[toggle title=”NR1″]
Subfamily of thyroid hormone receptors. Includes TR, RAR, VDR, PPAR, LXR, etc.
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RXR subfamily. Also includes, for example, HNF4.
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Subfamily of estrogen receptors. Includes ER, AR, GR, etc.
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Minor subfamily. Includes NGFI-B or NURR1.
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Minor subfamily. Includes those receptors related to FTZ-F1.
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Subfamily with only one member: GCNF1
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Subfamily of receptors that do not contain a DNA-binding domain: DAX-1 and SHP.
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According to the Discovery of their Ligand
Nuclear receptors have also been classified according to the history of their discovery: specifically, according to whether the ligand was described first and the receptor second, the receptor was described first and the ligand second, or the ligand remains unknown. This criteria might not seem very functional, yet it partially matches the receptor’s affinity towards its ligands and its intracellular behavior.
Thus, we can classify receptors into endocrine, “adopted”, and “orphan”.
Endocrine
They have a high affinity for steroid hormones (such as androgens, estrogens, or glucocorticoids).
In absence of ligand, they are located in the cytoplasm and bound to HSPs, that is, heat shock proteins. Ligand binding conditions the dissociation of HSP, its translocation into the nucleus and its dimerization.
Adopted
They have a lower affinity for their ligands.
In absence of ligand, they are permanently bound to their DNA response elements, they usually form heterodimers with RXR, and they associate with corepressors. The incorporation of ligand changes the associations: corepressors are separated and coactivators recruited.
They are called ”adopted” because they were first described according to their homology with endocrine receptors, but their ligand was unknown. They were ”orphan” receptors. Their ligand was identified in subsequent studies, and thus they became “adopted”. However, some ligands remain unidentified. Therefore, there is still a group of “orphan” receptors.
Orphan
The ligand of these receptors is yet to be identified. Such is the case of ERR or SF1. At a functional level, some of them act as dimers, while others seem to remain monomers.
According to their Molecular Mechanism
Nuclear receptors can be classified according to their mode of action. This classification partially overlaps with the classification based on the discovery of the ligands.
According to this classification, there are four types of nuclear receptors: I, II, III, and IV
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[tab title=”Type I”]
Receptors that, in absence of ligand, are located in the cytoplasm and associated with HSPs.
Ligand binding releases them from the HSPs, and allows their translocation into the nucleus and their homodimerization (the binding of two identical receptors). The binding to the DNA cause the recruitment of transcriptional coactivators.
Does this mechanism sound familiar? It is the same mechanism described in the previous classification of endocrine receptors. This subtype includes GR, ER, AR, etc.
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[tab title=”Type II”]
Receptors that, in absence of ligand, are located in the nucleus, bound to DNA, and form heterodimers, usually with RXR. In this configuration, they recruit corepressors.
Wait a minute, this also rings a bell: it is the same mechanism described for “adopted” receptors in the previous classification. This subtype includes TR and RAR.
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[tab title=”Type III”]
They are like type I receptors, but they recognize direct repeat HREs.
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[tab title=”Type IV”]
They are like type I receptors, but they recognize HREs with only one sequence and, therefore, act as monomers.
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Images: Andrew Smith, Brianna Lehman
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[icon style=”default” size=”20″]fa-chevron-left[/icon] All that Activates Is Not a Ligand
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Functions and Ubiquity [icon style=”default” size=”20″]fa-chevron-right[/icon]
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