What is Nuclear Hormone Receptor Proteins？
Nuclear hormone receptor proteins refer to a class of ligand-activating proteins. When they bind to specific sequences of DNA, they become transcription switches in the nucleus of the cell. These switches control the development and differentiation of skin, bone, and behavioral centers in the brain, as well as regulating reproductive tissue. Nuclear hormone receptors are ligand-activated transcription factors, which are trans-acting factors that regulate gene expression by interacting with specific DNA sequences upstream of the target gene. It works through a two-step mechanism. The first step is activation, which is achieved through hormone binding; the second step is receptor binding to DNA and transcriptional regulation.
Figure 1. Regulation of NHR. The NTD AF1 uses certain specific cofactors (BP1-n). AF2 in the LBD also interacts with the same or different specific cofactors (BP2). A bridge between AF1 and AF2 is formed by the assembly of additional cofactors (BPx). (AF1 and AF2 may also interact directly.) These interactions may be influenced by posttranscriptional modifications. Expression of cofactors and specific NHR ligands influence the AF1 and AF2 interactions. In turn, this probably results in various functional interactions with the basal transcription machinery to initiate transcription. AF, Activation function; BP, binding partner; DBD, DNA binding domain; ER, estrogen receptor; LBD, ligand-binding domain; NHR, nuclear hormone receptor; NTD, N-terminal domain. AF2 domain at the C terminus of the LBD of the NHRs, the NTD AFs are termed AF1, AF3.
Nuclear hormone receptor protein is composed of multiple domains. These domains are conserved and have different roles in different receptors. Including variable N-terminal region, conserved DNA binding domain (DBD), A variable hinge region (shows little homology within the nuclear receptor superfamily, has no known function), a conserved ligand binding domain (LBD), and a variable C-terminal region (has no known function). The general regulation process of NHR is shown in Fig. 1. However, NHRs may be tethered to DNA sites by way of other transcription factors, it is possible that additional configurational changes in the NTD AFs could be occurring by way of those connections (Fig. 2).
Figure 2. Regulation of NHR through other transcription factors (TFS)
Structures of NHR
1. N-Terminal Domains of NHR
The N-terminal domains (NTDs) have strong transcription-activating functions (AFs). Recombinant NTD-AFs can be folded by applying certain osmotic cells or by binding DNA binding regions to DNA response elements. The sequence of the DNA binding site may affect the functional status of the AFs domain. If properly folded, NTD-AFs can bind certain cofactors and primary transcription factors. Through these and / or direct interactions, NTD-AFs can interact with ligand binding of the NHRs, and interact with the AF2 domain in the carboxy-terminal portion.
2. DNA Binding Domain (DBD) of NHR
Central DBD plays a role in localizing the receptor to its hormone response element (HRE). The DNA-binding domain is a type II zinc finger motif and includes two subdomains, each containing a zinc ion, coordinated by four cysteine residues, and then an alpha helix. DBD binds as a dimer to each monomer that recognizes a six base pair sequence of DNA. The read helix of each monomer makes sequence-specific contacts in the main DNA groove at each half-site. These allow the dimer to distinguish the sequence by reading the sequence, spacing, and orientation of the half-sites within its response element. These proteins show flexibility in recognizing DNA sequences and can also be replaced by various amino acids in their reading helix without affecting binding.
3. Ligand Binding Domain (LBD) of NHR
LBD is involved in a variety of activities including hormone binding, formation of homodimers and heterodimers, formation of heat shock protein complexes, and transcriptional activation and suppression. The combination of hormones causes conformational changes that control these properties and affect gene expression. The conformational changes that accompany the transition between linked and unlinked forms of nuclear hormone receptors greatly affect their affinity for other proteins.
Figure 3. Structure of three different conformational states of nuclear receptor ligand-binding domains (LBDs). (a) The unliganded (apo) retinoid X receptor (RXR) LBD. (b) The agonist-bound (holo) retinoic acid receptor (RAR) LBD. (c) The antagonist-bound RAR LBD.
Coactivators of Nuclear Hormone Receptors
Coactivator proteins are necessary for maximal gene activation by the receptors. Coactivators act as a bridge between DNA bound receptor and basal transcription factors of the preinitiation complex, contributing to increased transcriptional activity of the target gene. Most of the coactivators could coactivate a wide variety of nuclear hormone receptors. Nuclear receptor coactivators promote the transcriptional activity of nuclear receptors, including estrogen receptor and progestin receptor. Nuclear receptor coactivators influence receptor transcription through a variety of mechanisms, including acetylation, methylation, phosphorylation and chromatin remodeling. Many nuclear hormone receptor coactivators have been reported. Researches show that the nuclear hormone receptor coactivator SRC-1(steroid receptor coactivator-1) is a specific target of p300; E6-associated protein (E6-AP/UBE3A) interacts with and coactivates the transcriptional activity of the human progesterone receptor (PR) in a hormone-dependent manner. E6-AP co-activates the hormone-dependent transcriptional activities of the other members of the nuclear hormone receptor superfamily; Familial focal segmental glomerulosclerosis (FSGS)-linked α-actinin 4 (ACTN4) protein can also function as transcriptional co-activators. Nuclear receptor coactivators are crucial in the fine-tuning of steroid-responsiveness in cells. Understanding the involvement of different coactivator and corepressor complexes to the promoter, is essential to understanding the way hormones function in the brain and how the complex behaviors regulated.
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