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Thyroid Hormone Receptors

Ronald J. Koenig

10.1002/cphy.cp070523

Source: Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth

Originally published: 1999

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 3,5,3′ Triiodo‐L‐Thyronine (T3) Receptors: Overview
2 T3 Receptor Functional Unit on DNA
2.1 Retinoid X Receptors
2.2 Other Potential Heterodimerization Partners
3 Structure and Function of the DNA Binding Domain
4 Structure and Function of the Ligand Binding Domain
5 Activity of Unliganded T3 Receptors
6 Activation of Transcription by T3
7 Activation of Transcription by Unliganded T3 Receptors
8 Repression of Transcription by T3
9 Phosphorylation of T3 Receptors
10 Summary
Figure 1. Figure 1.

Structures of thyroxine (T4) and T3.
Figure 2. Figure 2.

Nuclear receptor (erbA) superfamily of transcription factors. Schematic representations of several protein members of the nuclear receptor superfamily are shown, with the DNA binding domains and ligand binding domains noted. GR, glucocorticoid receptor; MR, mineralocorticoid receptor; PR, progesterone receptor; AR, androgen receptor; ER, estrogen receptor; VDR, vitamin D receptor; TRα, T3 receptor alpha 1; RARα, retinoic acid receptor alpha. The numbers within the DNA and ligand binding domains represent the percent amino acid identity of those domains relative to the GR. The DNA binding domain is the most highly conserved feature of these proteins. The ligand binding domains are generally conserved in size and show primary sequence conservation if the ligands are structurally similar. A hinge region separates the DNA and ligand binding domains (not demarcated in this figure). There is no sequence homology among the amino terminal domains. Protein dimerization domains are found within the DNA and ligand binding domains 3,92,103,110. Transcriptional activation domains are found within the ligand binding domains 26 and sometimes within the amino‐terminal region 128. Nuclear localization signals (which specify that the protein is to be transported into the nucleus) have not been thoroughly studied in all cases, but in at least some receptors they appear to be just carboxy terminal to the zinc fingers, within the hinge region 25,79.
Figure 3. Figure 3.

Schematic representation of thyroid hormone receptor gene products. The TRα gene encodes three proteins: TRα1, TRvα2, and TRvα3. TRα1 is a bona fide T3 receptor 410 amino acids in length; the DNA and ligand binding domains are demarcated. Alternative splicing after amino acid 370 results in the formation of two variant proteins, TRvα2 and TRvα3, that are not capable of binding T3 and hence are not T3 receptors. TRvα3 is 39 amino acids smaller than TRvα2 because it uses an alternative splice acceptor site. The TRβ gene encodes two bona fide TRs that differ from each other only in their amino‐terminal domains. These proteins derive from the use of alternative promoters and first exons. There is no primary sequence homology between the amino‐terminal regions of TRβ1, TRβ2, and TRα. The DNA and ligand binding domains of the TRβs are ∼85% identical to those of TRα1.
Figure 4. Figure 4.

Schematic representation of retinoid X receptor gene products. Three distinct genes encode the proteins RXRα, RXRβ, and RXRγ. These proteins are closely related to each other in their DNA and ligand binding domains, but not in their amino‐terminal regions. The RXRs are more distantly related to retinoic acid receptors, illustrated by RARβ. The numbers represent percent amino acid identity relative to RXRβ.
Figure 5. Figure 5.

Crystal structure of the RXR DBD‐TR DBD heterodimer bound to a direct repeat TRE. RXRα DBD (A) and TRβ DBD (B) show the Cys‐Zn coordination and alpha helices, which are in green. The numbering is relative to the first Zn‐coordinating cysteine of the DBD (for RXR, Cys‐1 is residue 135 of the full‐length protein; for TR, Cys‐1 is residue 107). The DBDs are composed of two modules, which are indicated by brackets. Two structural elements of the TR are demarcated, the A‐helix comprising residues 74–97, and the T region, which is the connector loop (residues 67–74) between the TR core DBD and the A‐helix. Disordered regions at the N and C termini are indicated by the dashed lines, and cloning artifacts from the expression vectors are indicated by small letters. Receptor–DNA interface: solid arrows indicate residues that make direct base contacts in the RXR (red) or TR (blue). Solid rectangles indicate residues that make direct phosphate contacts for RXR (red) or TR (blue). Open symbols indicate water‐mediated hydrogen bonds to the bases (open arrows) and the phosphates (open rectangles). RXR–TR Interface: Residues that make the dimer interface are shown with circles containing the letter D, with the shading indicating the pairings between residues that form the interaction between the RXR and TR DBDs. C: The sequence of the DNA used in crystallization. The consensus half‐sites are in green. The symbols indicate contacts with RXR (red) and TR (blue) as in Figure 5A and B.

From Rastinejad et al. 103 with permission
Figure 6. Figure 6.

The dimer interface of the RXR DBD (red) and the TR DBD (blue) seen in the crystal structure. Only residues participating are shown. Hydrogen bonds between subunits are shown as dotted lines.

From Rastinejad et al. 103 with permission
Figure 7. Figure 7.

Amino acid sequence of the ninth heptad of several nuclear hormone receptors. The numbers represent the amino acid residue positions within the intact proteins. TR, T3 receptor; RAR, retinoic acid receptor; VDR, vitamin D receptor; PPAR, peroxisome proliferator‐activated receptor; COUP‐TF, chicken ovalbumin upstream promoter transcription factor; Rev‐erb, reverse erbA. All sequences are human in origin.
Figure 8. Figure 8.

Comparison of the LBD sequences for rat TRα1, human TRβ, and human RXRα. The amino acid sequences of the rTRα1 and hRXRα LBDs are 21% identical and 47% similar. The secondary structure elements observed for rTRα1 and hRXRα LBDs are shown above the sequence, with alpha helices designated in blue and beta strands in yellow. Residues that contact the hormone are shown in purple. The motif near the carboxy terminus implicated in transcriptional activation, ΦΦXEΦΦ, where Φ represents a hydrophobic residue, is boxed in green.

From Wagner et al. 138 with permission
Figure 9. Figure 9.

Ligand is buried deep within the core of the TRα1 LBD. A: Ribbon drawing of the TRα1 LBD. The hydrophobic core of the receptor is formed by two alpha helices and the hormone. The hormone is depicted as a space‐filling model in magenta. Core‐forming elements are also shown in magenta. B: The hormone is completely buried within the receptor. Two cross sections of a space‐filling model demonstrate that the hormone is tightly packed within the receptor. The left panel is a cross section of the view in Figure 9A; the right panel is a cross section of a view rotated 90° about the horizontal from that in Figure 9A.

From Wagner et al. 138 with permission
Figure 10. Figure 10.

Schematic diagram of the hormone binding pocket. Residues that interact with hormone appear at approximately the site of interaction. Hydrogen bonds are shown as broken lines between the bonding partners; distances for each bond are listed. Nonbonded contacts are shown as radial spokes, which face towards interacting atoms. Only three direct hydrogen bonds are made: from Arg228 and Ser277 to the carboxylate group, and from His381 to the phenolic hydroxyl. The ether oxygen is found in a hydrophobic environment, surrounded by Phe218, Leu276, Leu287, and Leu292. Contacts to the inner ring are provided by the following side chains: Ile221, Ile222, and Ala225 from helix 3; Met259, Ser260, Arg262, and Ala263 from helix 5; and Leu276 from the loop between strands 3 and 4. Ser260 and Ile299; and Phe218, Ile221, and Ile222 form pockets for the 3‐and 5‐methyl substituents, respectively. Contacts to the outer ring are provided by Phe215, Phe218, and Phe401. Other side chain contacts are made by Gly290–1 and Leu292 from the loop between helices 7 and 8, His381 and Met 388 from helix 11, and Ile222 and Thr219 from helix 3. Gly290 and Gly291 form a pocket for the 3′‐isopropyl substituent.

From Wagner et al. 138 with permission
Figure 11. Figure 11.

Model for repression of gene activation by unliganded TR and activation by T3‐occupied TR. A: A heterodimer between RXR and unliganded TR binds to a TRE. The hinge region of the unliganded TR and RXR binds to a co‐repressor protein (for example, N‐CoR or SMRT) which binds sin3a. Sin3a, in turn, binds histone deacetylases. Transcription is repressed by histone deacetylation, and perhaps other mechanisms. A similar model could be invoked for unliganded TR homodimers, especially on high‐affinity homodimer binding sites. B: Binding of T3 to the TR results in an LBD conformational change, such that binding of the co‐repressor is sterically precluded but binding of a co‐activator complex is favored. In this model, the co‐activator complex includes a p160 family member (e.g. SRC‐1 or PCIP), CBP, and PCAF. Transcription is activated by histone acetylation, and perhaps other mechanisms. If the unliganded TR bound to a TRE as a homodimer (as with an IP TRE), T3 occupancy would cause the homodimer to fall off the DNA, allowing binding of the RXR‐TR heterodimer and interaction with co‐activators (not shown). However, certain TREs may be activated by TR homodimers 93.


Figure 1.

Structures of thyroxine (T4) and T3.



Figure 2.

Nuclear receptor (erbA) superfamily of transcription factors. Schematic representations of several protein members of the nuclear receptor superfamily are shown, with the DNA binding domains and ligand binding domains noted. GR, glucocorticoid receptor; MR, mineralocorticoid receptor; PR, progesterone receptor; AR, androgen receptor; ER, estrogen receptor; VDR, vitamin D receptor; TRα, T3 receptor alpha 1; RARα, retinoic acid receptor alpha. The numbers within the DNA and ligand binding domains represent the percent amino acid identity of those domains relative to the GR. The DNA binding domain is the most highly conserved feature of these proteins. The ligand binding domains are generally conserved in size and show primary sequence conservation if the ligands are structurally similar. A hinge region separates the DNA and ligand binding domains (not demarcated in this figure). There is no sequence homology among the amino terminal domains. Protein dimerization domains are found within the DNA and ligand binding domains 3,92,103,110. Transcriptional activation domains are found within the ligand binding domains 26 and sometimes within the amino‐terminal region 128. Nuclear localization signals (which specify that the protein is to be transported into the nucleus) have not been thoroughly studied in all cases, but in at least some receptors they appear to be just carboxy terminal to the zinc fingers, within the hinge region 25,79.



Figure 3.

Schematic representation of thyroid hormone receptor gene products. The TRα gene encodes three proteins: TRα1, TRvα2, and TRvα3. TRα1 is a bona fide T3 receptor 410 amino acids in length; the DNA and ligand binding domains are demarcated. Alternative splicing after amino acid 370 results in the formation of two variant proteins, TRvα2 and TRvα3, that are not capable of binding T3 and hence are not T3 receptors. TRvα3 is 39 amino acids smaller than TRvα2 because it uses an alternative splice acceptor site. The TRβ gene encodes two bona fide TRs that differ from each other only in their amino‐terminal domains. These proteins derive from the use of alternative promoters and first exons. There is no primary sequence homology between the amino‐terminal regions of TRβ1, TRβ2, and TRα. The DNA and ligand binding domains of the TRβs are ∼85% identical to those of TRα1.



Figure 4.

Schematic representation of retinoid X receptor gene products. Three distinct genes encode the proteins RXRα, RXRβ, and RXRγ. These proteins are closely related to each other in their DNA and ligand binding domains, but not in their amino‐terminal regions. The RXRs are more distantly related to retinoic acid receptors, illustrated by RARβ. The numbers represent percent amino acid identity relative to RXRβ.



Figure 5.

Crystal structure of the RXR DBD‐TR DBD heterodimer bound to a direct repeat TRE. RXRα DBD (A) and TRβ DBD (B) show the Cys‐Zn coordination and alpha helices, which are in green. The numbering is relative to the first Zn‐coordinating cysteine of the DBD (for RXR, Cys‐1 is residue 135 of the full‐length protein; for TR, Cys‐1 is residue 107). The DBDs are composed of two modules, which are indicated by brackets. Two structural elements of the TR are demarcated, the A‐helix comprising residues 74–97, and the T region, which is the connector loop (residues 67–74) between the TR core DBD and the A‐helix. Disordered regions at the N and C termini are indicated by the dashed lines, and cloning artifacts from the expression vectors are indicated by small letters. Receptor–DNA interface: solid arrows indicate residues that make direct base contacts in the RXR (red) or TR (blue). Solid rectangles indicate residues that make direct phosphate contacts for RXR (red) or TR (blue). Open symbols indicate water‐mediated hydrogen bonds to the bases (open arrows) and the phosphates (open rectangles). RXR–TR Interface: Residues that make the dimer interface are shown with circles containing the letter D, with the shading indicating the pairings between residues that form the interaction between the RXR and TR DBDs. C: The sequence of the DNA used in crystallization. The consensus half‐sites are in green. The symbols indicate contacts with RXR (red) and TR (blue) as in Figure 5A and B.

From Rastinejad et al. 103 with permission


Figure 6.

The dimer interface of the RXR DBD (red) and the TR DBD (blue) seen in the crystal structure. Only residues participating are shown. Hydrogen bonds between subunits are shown as dotted lines.

From Rastinejad et al. 103 with permission


Figure 7.

Amino acid sequence of the ninth heptad of several nuclear hormone receptors. The numbers represent the amino acid residue positions within the intact proteins. TR, T3 receptor; RAR, retinoic acid receptor; VDR, vitamin D receptor; PPAR, peroxisome proliferator‐activated receptor; COUP‐TF, chicken ovalbumin upstream promoter transcription factor; Rev‐erb, reverse erbA. All sequences are human in origin.



Figure 8.

Comparison of the LBD sequences for rat TRα1, human TRβ, and human RXRα. The amino acid sequences of the rTRα1 and hRXRα LBDs are 21% identical and 47% similar. The secondary structure elements observed for rTRα1 and hRXRα LBDs are shown above the sequence, with alpha helices designated in blue and beta strands in yellow. Residues that contact the hormone are shown in purple. The motif near the carboxy terminus implicated in transcriptional activation, ΦΦXEΦΦ, where Φ represents a hydrophobic residue, is boxed in green.

From Wagner et al. 138 with permission


Figure 9.

Ligand is buried deep within the core of the TRα1 LBD. A: Ribbon drawing of the TRα1 LBD. The hydrophobic core of the receptor is formed by two alpha helices and the hormone. The hormone is depicted as a space‐filling model in magenta. Core‐forming elements are also shown in magenta. B: The hormone is completely buried within the receptor. Two cross sections of a space‐filling model demonstrate that the hormone is tightly packed within the receptor. The left panel is a cross section of the view in Figure 9A; the right panel is a cross section of a view rotated 90° about the horizontal from that in Figure 9A.

From Wagner et al. 138 with permission


Figure 10.

Schematic diagram of the hormone binding pocket. Residues that interact with hormone appear at approximately the site of interaction. Hydrogen bonds are shown as broken lines between the bonding partners; distances for each bond are listed. Nonbonded contacts are shown as radial spokes, which face towards interacting atoms. Only three direct hydrogen bonds are made: from Arg228 and Ser277 to the carboxylate group, and from His381 to the phenolic hydroxyl. The ether oxygen is found in a hydrophobic environment, surrounded by Phe218, Leu276, Leu287, and Leu292. Contacts to the inner ring are provided by the following side chains: Ile221, Ile222, and Ala225 from helix 3; Met259, Ser260, Arg262, and Ala263 from helix 5; and Leu276 from the loop between strands 3 and 4. Ser260 and Ile299; and Phe218, Ile221, and Ile222 form pockets for the 3‐and 5‐methyl substituents, respectively. Contacts to the outer ring are provided by Phe215, Phe218, and Phe401. Other side chain contacts are made by Gly290–1 and Leu292 from the loop between helices 7 and 8, His381 and Met 388 from helix 11, and Ile222 and Thr219 from helix 3. Gly290 and Gly291 form a pocket for the 3′‐isopropyl substituent.

From Wagner et al. 138 with permission


Figure 11.

Model for repression of gene activation by unliganded TR and activation by T3‐occupied TR. A: A heterodimer between RXR and unliganded TR binds to a TRE. The hinge region of the unliganded TR and RXR binds to a co‐repressor protein (for example, N‐CoR or SMRT) which binds sin3a. Sin3a, in turn, binds histone deacetylases. Transcription is repressed by histone deacetylation, and perhaps other mechanisms. A similar model could be invoked for unliganded TR homodimers, especially on high‐affinity homodimer binding sites. B: Binding of T3 to the TR results in an LBD conformational change, such that binding of the co‐repressor is sterically precluded but binding of a co‐activator complex is favored. In this model, the co‐activator complex includes a p160 family member (e.g. SRC‐1 or PCIP), CBP, and PCAF. Transcription is activated by histone acetylation, and perhaps other mechanisms. If the unliganded TR bound to a TRE as a homodimer (as with an IP TRE), T3 occupancy would cause the homodimer to fall off the DNA, allowing binding of the RXR‐TR heterodimer and interaction with co‐activators (not shown). However, certain TREs may be activated by TR homodimers 93.

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Article Title: Thyroid Hormone Receptors
 

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Ronald J. Koenig. Thyroid Hormone Receptors. Compr Physiol 2011, Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth: 737-755. First published in print 1999. doi: 10.1002/cphy.cp070523