Abstract
Nuclear receptor proteins constitute a superfamily of proteins that function as ligand dependent transcription factors. They are implicated in the transcriptional cascades underlying many physiological phenomena, such as embryogenesis, cell growth and differentiation, and apoptosis, making them one of the major signal transduction paradigms in metazoans. Regulation of these receptors occurs through the binding of hormones, and in the case of the retinoic acid receptor (RAR), through the binding of retinoic acid (RA). In addition to this canonical scenario of RAR activity, recent discoveries have shown that RAR regulation also occurs as a result of phosphorylation. In fact, RA induces non-genomic effects, such as the activation of kinase signaling pathways, resulting in the phosphorylation of several targets including RARs themselves. In the case of RARα, phosphorylation of Ser369 located in loop L9–10 of the ligand-binding domain leads to an increase in the affinity for the protein cyclin H, which is part of the Cdk-activating kinase complex of the general transcription factor TFIIH. The cyclin H binding site in RARα is situated more than 40 Å from the phosphorylated serine. Using molecular dynamics simulations of the unphosphorylated and phosphorylated forms of the receptor RARα, we analyzed the structural implications of receptor phosphorylation, which led to the identification of a structural mechanism for the allosteric coupling between the two remote sites of interest. The results show that phosphorylation leads to a reorganization of a local salt bridge network, which induces changes in helix extension and orientation that affects the cyclin H binding site. This results in changes in conformation and flexibility of the latter. The high conservation of the residues implicated in this signal transduction suggests a mechanism that could be applied to other nuclear receptor proteins.
Highlights
Nuclear receptors are ligand-dependent transcription factors that participate in many cellular signaling networks involved in various physiological phenomena, such as embryogenesis, cell differentiation, cell growth, reproduction and apoptosis [1]
The nuclear receptor RARa is an important player in the regulation of gene transcription and many structure-based studies corroborated the role of ligand binding in the regulatory mechanisms [33,34,35,36]
In a non-genomic cascade, retinoic acid (RA) triggers the activation of the MSK1 kinase, which phosphorylates serine 369 (S369) located in the ligand-binding domain (LBD)
Summary
Nuclear receptors are ligand-dependent transcription factors that participate in many cellular signaling networks involved in various physiological phenomena, such as embryogenesis, cell differentiation, cell growth, reproduction and apoptosis [1]. The superfamily of nuclear receptors includes the nuclear retinoic acid receptors (RARs), which bind retinoic acid (RA), the active metabolite of vitamin A and which function as heterodimers with a second family of nuclear receptors, the retinoid X receptors (RXRs). RARs and RXRs display a well-defined domain organization, composed mainly of an unstructured N-terminal domain (NTD) and two well-structured domains, a central DNA-binding domain (DBD) and a C-terminal ligand-binding domain (LBD). The LBD is formed by 12 a-helices and one b-sheet, which display the general three layer antiparallel helical sandwich fold found in the NR superfamily (see Figure 1)
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