Structural and molecular determinants of mineralocorticoid receptor signalling

Großmann, Claudia; Almeida-Prieto, Brian; Nolze, Alexander; Rosa, Diego Álvarez de la

doi:10.1111/bph.15746

Cited by 36 publications

(49 citation statements)

References 157 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have to mention, however, that importin 4 seems not to play a significant role for PR nuclear translocation in T47D cells, in contrast to its role for the nuclear transfer of AR, in both T47D and LnCaP cells, an element which needs further investigation. Therefore, our results (both in silico and in vitro ) confirm the primary role of importin α, as the primary karyopherin involved in the cytoplasmic-nuclear shuttle of steroid hormone receptors, in accordance with previous data ( 14 – 24 ). However, further research including mutagenesis experiments, is required for confirming our findings and to better determine the importance and function of each identified NLS motif, as the binding of co-regulatory molecules, or HSP might mask some of these sites.…”

Section: Discussionsupporting

confidence: 93%

“…In addition, another NLS at the LBD ( 15 ) has been described, which recognizes importin 4 (amino acids 685-689) or importin 5 (amino acids 781-784 and 927-930), as reported here. Finally, the mineralocorticoid receptor (MR) interacts with importin α ( 19 , 20 , 22 , 24 ). Moreover, two additional NLS sequences have been identified, one in the DBD and another in the LBD of the receptor ( 24 ), which, as reported here, are recognition sequences for importin 7.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, the mineralocorticoid receptor (MR) interacts with importin α ( 19 , 20 , 22 , 24 ). Moreover, two additional NLS sequences have been identified, one in the DBD and another in the LBD of the receptor ( 24 ), which, as reported here, are recognition sequences for importin 7.…”

Section: Discussionmentioning

confidence: 99%

“…However, it was later revealed to have several important functions. It is mainly responsible for the nuclear translocation of steroid receptors, since it contains (at the interface between DBD-hinge region) a specific amino acid sequence (Nuclear Localization Signal-NLS), recognized by importin α ( 14 – 24 ). Moreover, as it was found for estrogen receptor alpha (ERα), it possesses an intrinsic activity for calmodulin binding ( 25 ) and is the site of a number of post-translational modifications.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Importins involved in the nuclear transportation of steroid hormone receptors: In silico and in vitro data

et al. 2022

View full text Add to dashboard Cite

The nuclear receptor superfamily (NRS) consists of 48 receptors for lipophilic substances and is divided into 7 different subfamilies, with subfamily 3 comprising steroid hormone receptors. Several nuclear receptors usually bind their cognate ligands in the cytosol and the complex (mono- or dimerized) is transported to the nucleus, where it acts as a transcription initiating factor for a number of genes. The general structure of nuclear receptors consists of an N-terminal activating domain (A/B), important for the binding of activating or inhibitory co-factors, the DNA-binding domain (C), responsible for the association of the receptor-ligand-co-factor complex to the nucleus, the ligand-AF2 domain (E/F), where ligand binding occurs as well as that of ligand-dependent activating/inhibiting factors, and a flexible/non-structured domain (D), linking the DBD and LBD, called hinge region, on which a significant number of post-translational modifications occur. This hinge domain, for the sub-class of steroid receptors, is a non-structured domain and was reported as mainly responsible for the nuclear transport of steroid receptors, since it contains a specific amino acid sequence (Nuclear Localization Signal-NLS), recognized by importin α. In addition to the importin α/β complex, a number of other importins have been discovered and reported to be responsible for the nuclear transport of a number of significant proteins; however, the corresponding recognition sequences for these importins have not been identified. Recently, we have reported the identification of the NLS sequences for importins 4, 5 and 7. In this work, we provide in silico data, followed by experimental in vitro validation, showing that these alternative importins are responsible for the nuclear transportation of steroid hormone receptors such as ERα, AR and PR, and therefore they may consist of alternative targets for the pharmacological manipulation of steroid hormone actions. Moreover, we provide additional in silico data for the hinge region of steroid hormone receptors which is highly enriched with NLS sequences for importins 4, 5 and 7, in addition to the recognition NLS for importin α/β.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Importins involved in the nuclear transportation of steroid hormone receptors: In silico and in vitro data

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The MR also has activation function (AF) domains that are capable of binding tissue-specific coregulators. A dimerization domain is found within the DBD [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic Profiling of Glucocorticoid (NR3C1) and Mineralocorticoid (NR3C2) Receptor Polymorphisms before Starting Therapy with Androgen Receptor Inhibitors: A Study of a Patient Who Developed Toxic Myocarditis after Enzalutamide Treatment

2022

View full text Add to dashboard Cite

Enzalutamide is a nonsteroidal inhibitor of the androgen receptor (AR) signaling pathway and is used to treat patients with metastatic castration-resistant prostate cancer. However, the risk of cardiovascular-related hospitalization in patients with no contraindications for the use of enzalutamide is about 1–2%. To date, the underlying molecular basis of this has not been established. The androgen receptor, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are nuclear receptors that share structural similarities and have closely related DNA-binding sites and coregulators. In non-epithelial cells, a fine balance of the activities of these receptors is essential to ensure correct cellular function. In this study, we present a molecular characterization of these nuclear receptors in a prostate cancer patient who developed congestive heart failure after enzalutamide treatment. White cell RNAseq revealed a homozygous rs5522 MR polymorphism and both the rs143711342 and rs56149945 GR polymorphisms, carried in different alleles. No different specific splice isoforms were detected. Recent research suggests that AR inhibition by enzalutamide makes available a coregulator that specifically interacts with the rs5522-mutated MR, increasing its activity and producing adverse effects on cardiovascular health. We suggest an evaluation of the MR rs5522 polymorphism before starting therapy with AR inhibitors.

show abstract

The mineralocorticoid receptor forms higher order oligomers upon DNA binding

Fettweis,

Johnson,

Almeida‐Prieto

et al. 2024

Protein Science

Self Cite

View full text Add to dashboard Cite

The prevailing model of steroid hormone nuclear receptor function assumes ligand‐induced homodimer formation followed by binding to DNA hormone response elements (HREs). This model has been challenged by evidence showing that the glucocorticoid receptor (GR) forms tetramers upon ligand and DNA binding, which then drive receptor‐mediated gene transactivation and transrepression. GR and the closely‐related mineralocorticoid receptors (MR) interact to transduce corticosteroid hormone signaling, but whether they share the same quaternary arrangement is unknown. Here, we used a fluorescence imaging technique, Number & Brightness, to study oligomerization in a cell system allowing real‐time analysis of receptor‐DNA interactions. Agonist‐bound MR forms tetramers in the nucleoplasm and higher order oligomers upon binding to HREs. Antagonists form intermediate‐size quaternary arrangements, suggesting that large oligomers are essential for function. Divergence between MR and GR quaternary structure is driven by different functionality of known and new multimerization interfaces, which does not preclude formation of heteromers. Thus, influencing oligomerization may be important to selectively modulate corticosteroid signaling.

show abstract

Structural and molecular determinants of mineralocorticoid receptor signalling

Cited by 36 publications

References 157 publications

Importins involved in the nuclear transportation of steroid hormone receptors: In silico and in vitro data

Importins involved in the nuclear transportation of steroid hormone receptors: In silico and in vitro data

Genetic Profiling of Glucocorticoid (NR3C1) and Mineralocorticoid (NR3C2) Receptor Polymorphisms before Starting Therapy with Androgen Receptor Inhibitors: A Study of a Patient Who Developed Toxic Myocarditis after Enzalutamide Treatment

The mineralocorticoid receptor forms higher order oligomers upon DNA binding

Contact Info

Product

Resources

About