Thyroid hormone receptor

The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcriptionand translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response. The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcriptionand translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response. There are four domains that are present in all TRs. Two of these, the DNA-binding (DBD) and hinge domains, are involved in the ability of the receptor to bind hormone response elements( HREs). TRs also have a ligand binding domain (LBD) that allows them to bind to thyroid hormone with high affinity. The fourth domain is a transactivation domainwhich allows the receptor to bind transcription factors. Thyroid hormone receptors play critical roles in the regulation of metabolism, heart rate, and development of organisms. These receptors are typically associated with retinoic acid receptors (RXR), forming heterodimers. In its inactivated form, the TR inhibits gene transcription by binding corepressors. This adds an additional level of regulation to an already tightly regulated process. When activated, these receptors become associated with other activators and initiate gene transcription. TRs are also involved in cell viability, and are believed to have other non-genomic affects that are currently being investigated. Thyroid hormone is transported into the cell through a transporter. Once inside of the cell, the hormone can have genomic or non-genomic effects. The genomic signaling pathway directly influences gene transcription and translation, while the non-genomic pathway involves more rapid, cellular changes. Thyroid hormone receptors regulate gene expression by binding to hormone response elements (HREs) in DNA either as monomers, heterodimers with other nuclear receptors, or homodimers. Dimerizing with different nuclear receptors leads to the regulation of different genes. THR commonly interacts with the retinoid X receptor (RXR), a nuclear retinoic acid receptor. TR/RXR heterodimers are the most transcriptionally active form of TR. Retinoic acid receptors are located in the nucleus and commonly form complexes with steroid hormone receptors in order to regulate the production of essential gene products. Retinoic acid receptors bind corepressorsin the absence of their ligand, retinoic acid, which is formed from the metabolism of vitamin A. Retinoid X receptors are activated by binding to 9-cis-retinoic acid, a specific isomer of retinoic acid. Other retinoic acid receptors are less specific, allowing them to bind isomers of retinoic acid with similar affinities. Once RXRs bind ligand, they undergo conformational changes that reduce their affinity for corepressors—allowing them to attract coactivators to the transcription site. Once all of the necessary cofactors are present, the presence of a DNA binding domain permits the binding of response elements, initiating gene transcription. Due to their role in gene regulation, studies have shown that these receptors are necessary for growth and development. In the absence of hormone, TR forms a complex with corepressor proteins such as nuclear receptor co-repressor 1 (N-CoR) and 2 (N-CoR2). While these cofactors are present, TR binds HREs in a transcriptionally inactive state. This inhibition of gene transcription allows for tight regulation of gene products. Binding of thyroid hormone results in a conformational change in helix 12 of the TR transactivation domain, which displaces the corepressors from the receptor/DNA complex. Coactivator proteins are recruited, forming a DNA/TR/coactivator complex. One coactivator recruited to the site is nuclear receptor co-activator 1 (NCoA-1). RNA polymerase is recruited to the site and transcribes downstream DNA into messenger RNA (mRNA). The mRNA generated is then translated into the corresponding proteins. The protein products from this process drive the changes in cell function observed in the presence of thyroid hormone.