Structural and functional analysis of domains of the progesterone receptor

Abstract

Steroid hormone receptors are multi-domain proteins composed of conserved well-structured regions, such as ligand (LBD) and DNA binding domains (DBD), plus other naturally unstructured regions including the amino-terminal domain (NTD) and the hinge region between the LBD and DBD. The hinge is more than just a flexible region between the DBD and LBD and is capable of binding co-regulatory proteins and the minor groove of DNA flanking hormone response elements. Because the hinge can directly participate in DNA binding it has also been termed the carboxyl terminal extension (CTE) of the DNA binding domain. The CTE and NTD are dynamic regions of the receptor that can adopt multiple conformations depending on the environment of interacting proteins and DNA. Both regions have important regulatory roles for multiple receptor functions that are related to the ability of the CTE and NTD to form multiple active conformations. This review focuses on studies of the CTE and NTD of progesterone receptor (PR), as well as related work with other steroid/nuclear receptors.

Steroid Receptors in the Uterus and Ovary

“…17 Phosphorylation of the A/B domain is the most well-characterized posttranslational modification and occurs in all three sex steroid receptors via the actions of multiple intracellular signaling pathways, including mitogen-activated protein kinase pathways, 49 the cAMP/protein kinase A (PKA) pathway, and cyclin-dependent kinases. 12,37,39,43,50 The extended N-terminal sequences that are unique to PRB (Figure 25.1) provide a third transcriptional AF-3 domain in this isoform that is lacking in PRA. This may allow for PRB-specific expression of certain P regulated 4.…”

“…FEMALE REPRODUCTIVE SYSTEM genes. 29,50,60 In general, PRB is a stronger activator of transcription versus PRA when acting on a hormone response element (HRE)-driven gene construct in vitro. 60 Furthermore, antagonist-bound PRB acts as a strong transcriptional activator in certain cell and promoter contexts, whereas antagonist-bound PRA is inactive.…”

“…In contrast, receptor antagonists are unable to induce a similar repositioning of H12, leading to a receptor formation that is incompatible with co-activator recruitment and is therefore less likely to activate transcription. The LBDs of PRB and PRA are identical and provide for high affinity binding to P. 12,50 The LBD of the AR in humans, rats, and mice is identical and provides for high affinity binding of two endogenous androgens, T and 5α-hydroxyT (DHT), the latter of which binds with much greater affinity. 38,66 Numerous high affinity synthetic ligands for PR and AR have been developed, including the agonists R5020 and R1181, respectively (Table 25.2).…”

“…50,60 Furthermore, PRA can repress the transcriptional activities of PRB in certain cell and promoter contexts, 50 suggesting that PRA may modulate P responsiveness in certain tissues. Interestingly, PRA can also repress the actions of other heterologous NRs, including the AR, ER, and GR.…”

FOXA1 Promotes Tumor Cell Proliferation through AR Involving the Notch Pathway in Endometrial Cancer

“…The PR exists in two primary isoforms, differing structurally by the inclusion of an N-terminal segment unique to the fulllength isoform, PR-B [2] (Figure 1). This region, termed the B-upstream segment, is missing from the shorter isoform, PR-A [3]. The two isoforms are encoded by the same gene (regulated by distinct but tandem upstream promoters) and are most often co-expressed [4].…”