Molecular and Cellular Endocrinology 408 (2015) 33–37

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Molecular and Cellular Endocrinology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / m c e

Review

Novel interactions of the mineralocorticoid receptor Peter J. Fuller * MIMR-PHI Institute (formerly Prince Henry’s Institute of Medical Research), Clayton, Victoria, Australia

A R T I C L E

I N F O

Article history: Received 12 November 2014 Received in revised form 17 January 2015 Accepted 18 January 2015 Available online 7 February 2015 Keywords: Corticosteroids Coactivators N/C-interaction Aldosterone Cortisol

A B S T R A C T

The mineralocorticoid receptor (MR) differs from the other steroid receptors in that it responds to two physiological ligands, aldosterone and cortisol. In epithelial tissues, aldosterone selectivity is determined by 11β-hydroxysteroid dehydrogenase type II. In other tissues cortisol is the primary ligand; in some tissues cortisol may act as an antagonist. To better target MR, an understanding of the structural determinants of tissue and ligand-specific MR activation is required. Our focus is on interactions of the ligand-binding domain (LBD) with ligand, the N-terminal domain and putative co-regulatory molecules. Molecular modelling has identified a region in the LBD of the MR and indeed other steroid receptors that critically defines ligand-specificity for aldosterone and cortisol, yet is not part of the ligandbinding pocket. An interaction between the N-terminus and LBD observed in the MR is aldosteronedependent but is unexpectedly antagonised by cortisol. The structural basis of this interaction has been defined. We have identified proteins which interact in the presence of either aldosterone or cortisol but not both. These have been confirmed as coactivators of the full-length hMR. The structural basis of this interaction has been determined for tesmin, a ligand-discriminant coactivator of the MR. The successful identification of the structural basis of antagonism and of ligand-specific interactions of the MR may provide the basis for the development of novel MR ligands with tissue specificity. © 2015 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8.

Introduction ........................................................................................................................................................................................................................................................... MR signalling mechanisms .............................................................................................................................................................................................................................. MR tissue distribution ....................................................................................................................................................................................................................................... Ligand specificity for the MR ........................................................................................................................................................................................................................... Mechanisms of ligand binding specificity .................................................................................................................................................................................................. Interdomain interactions .................................................................................................................................................................................................................................. MR co-regulators ................................................................................................................................................................................................................................................. Conclusions ............................................................................................................................................................................................................................................................ Acknowledgements ............................................................................................................................................................................................................................................. References ..............................................................................................................................................................................................................................................................

1. Introduction Aldosterone and the mineralocorticoid receptor (MR) are classically viewed as mediating the regulation of epithelial sodium transport in the distal nephron and distal colon (Fuller and Young, 2005). The MR is a member of the nuclear receptor superfamily. Its closest homologies are with the other corticosteroid receptor, the glucocorticoid

Proceedings of the Adrenal Cortex Conference, Chicago, USA. * MIMR-PHI Institute, 27-31 Wright Street, Clayton, Victoria 3168, Australia. Tel.: +61 3 9594 4379; fax: +61 3 9594 6125. E-mail address: [email protected] http://dx.doi.org/10.1016/j.mce.2015.01.027 0303-7207/© 2015 Elsevier Ireland Ltd. All rights reserved.

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receptor (GR). The MR is unique amongst the steroid receptors in having two physiological ligands, aldosterone and cortisol (corticosterone in rodents); indeed progesterone which is antagonist at the MR may also be viewed as a physiological ligand. Given that cortisol binds the MR with an equivalent affinity to that of aldosterone, yet it circulates at concentrations over 100-fold higher than that of aldosterone, access of aldosterone to the MR under normal physiological conditions would be precluded were it not for the presence of the enzyme 11βhydroxysteroid dehydrogenase type 2 (HSD2). HSD2 metabolises cortisol to cortisone which in contrast to cortisol is unable to bind or activate the MR (Odermatt and Kratschmar, 2012). As with other nuclear receptors, the MR consists of 3 principal domains. The first is a relatively unstructured N-terminal domain,

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which is poorly conserved across the various receptors and whose key structural property is arguably this lack of structure (Fischer et al., 2010). Of all the nuclear receptors, the MR has the longest N-terminal domain. This lack of structure is thought to confer promiscuity of interaction upon the receptor. A central DNA-binding domain (DBD) of 66 or 68 amino acids defines the nuclear receptor superfamily. It is relatively highly conserved both from a functional and structural perspective. The crystal structure of the MR DBD has recently been solved (Hudson et al., 2014). It largely matches the structure of the closely related GR (Luisi et al., 1991) with which it shares considerable sequence homology; however there are subtle differences which may impact signalling (Hudson et al., 2014). At the C-terminal of the receptor is the ligandbinding domain (LBD) which also shares significant homology within the steroid receptor subfamily of the nuclear receptors (androgen receptor (AR), progesterone receptor (PR) and GR). Both the N-terminal domain and the LBD contain activation functions (AF-1 and AF-2 respectively). These activation functions mediate the interaction with the transcriptional apparatus. The MR LBD of 251 amino acids consist of 11α-helices (labeled by convention 1–12; helix 2 is unstructured in the MR) and 4 β-strands (Bledsoe et al., 2005; Fagart et al., 2005; Li et al., 2005). The structural representation of the AF-2 function is formed by helices 3, 4, 5 and 12. This region as with other nuclear receptors is able to bind co-regulatory molecules containing the leucine-x-x-leucine-leucine-motif (LxxLL: where x is another amino acid) characteristic of a number of coactivator molecules (Gronemeyer et al., 2004).

2. MR signalling mechanisms The classical model of MR signalling sees the hydrophobic ligand move into the cytoplasm where it interacts with the unliganded receptor. In the absence of ligand, the receptor is complexed with a heat-shock binding (hsp) complex which holds it in a transcriptionally inactive but high affinity binding state. Binding of ligand sees a significant conformational change with helix 12 moving into position that forms the AF-2 domain. With this confirmational change and a variable degree of dissociation of proteins in the hsp complex, the receptor translocates to the nucleus where it binds to specific response elements, often a palindromic inverted repeat in the regulatory region of target genes. The DNA-bound, activated receptor then recruits the coregulatory complexes which link the receptor to the transcriptional apparatus, resulting in either activation or potentially repression of target gene expression (Glass and Rosenfeld, 2000). Although a number of MR regulated genes have now been identified, a broader whole-of-system picture of MRregulated genes has not yet been developed in the way it has been for a number of other nuclear receptors, including the GR (Bookout et al., 2006). For other steroid receptors particularly the GR, signalling may also occur through protein-protein interaction with other transcription factors. This may involve a process of sequestration. It is often termed transrepression or tethering (De Bosscher et al., 2003). The best characterised example is between the GR and the transcription factors AP-1 and NFκB, a key component of the GRmediated anti-inflammatory effect. Similar mechanisms have also been described for the estrogen receptors (ER) where again the interaction can be with NFκB. In contrast to the GR, transrepression by the MR has not been clearly established. The MR does not interact with AP-1 (Pearce and Yamamoto, 1993) and although an interaction has been reported with the NFκB subunits in vitro (Kolla and Litwack, 2000; Liden et al., 1997), the finding somewhat contradicts results from other studies (Leroy et al., 2009; Terada et al., 2012; Wissink et al., 2000). NFκB activation stimulates expression of the adhesion molecule ICAM-1 (Caldenhoven et al., 1995) as does

MR activation (Caprio et al., 2008) whereas the GR transrepresses these responses (Caldenhoven et al., 1995). It is also counterintuitive that the MR might transrepress inflammatory signalling pathways given the large body of work which demonstrates the effects of MR activation to be pro-inflammatory in the cardiovascular system and kidney (Young and Rickard, 2012), including activation of the canonical NFκB signalling pathway (Leroy et al., 2009; Terada et al., 2012). More recently Chantong et al. (2012) have directly contrasted the influence of the MR and the GR on NFκB signalling in microglial cells. They found that MR activated and GR repressed NFκB signalling in this system. This is consistent with the concept that MR activation is pro-inflammatory, occurring at physiological concentrations of cortisol i.e. early in the response whereas higher concentrations of cortisol, acting through the GR, serve to limit and modulate the inflammatory response. Repression of 5HT1A receptor gene expression in the hippocampus by MR activation is however thought to be mediated by transrepression (Meijer et al., 2000). The third putative mechanism of MR signalling is so-called nongenomic or rapid signalling where the activated MR interacts at the cell membrane to modify the response of second messenger pathways. Interactions with the epidermal growth factor receptor have been well characterised (Grossmann and Gekle, 2012) as have interactions with a range of other signalling pathways (Dooley et al., 2012). The G-protein coupled receptor, GPR30, a member of the seven transmembrane domain family of cell surface receptors, has been reported to be a membrane receptor for aldosterone (Feldman and Gros, 2013); it has also been invoked as a membrane receptor for estrogen where it seems likely to be acting more as a coreceptor for the classical estrogen receptor than the actual receptor per se (Levin, 2009).

3. MR tissue distribution In addition to the aforementioned epithelia, the MR is expressed in an extensive range of tissues, many of which are neither epithelial nor associated with sodium transport. These include high abundance expression in the hippocampus where the receptor appears likely to have a range of effects on memory and affect, as well as in the hypothalamus (Fuller and Young, 2005). Its role in the cardiovascular system has recently been extensively examined and indeed is a major focus given the adverse effects of mineralocorticoid excess on the cardiovascular system (Young and Rickard, 2012). The MR also plays a central role in adipocyte biology (Marzolla et al., 2012) and is expressed in a range of reproductive tissues where its physiological role is yet to be characterised. The MR is expressed in a range of inflammatory cells, particularly the monocyte-macrophage lineage where tissuespecific knockout of the MR in transgenic mice has provided particularly striking insights into the biology of the MR in these tissues (Rickard et al., 2009). In many of these tissues, aside from the distal nephron and colon and the vasculature (Fuller and Young, 2005) and a discreet subpopulation of hypothalamic neurones involved in salt appetite (Geerling and Loewy, 2009), the MR is largely expressed in the absence of HSD2 and is therefore likely to be playing a role as a second receptor for cortisol, particularly in the brain where aldosterone is thought to cross the blood brain barrier poorly, if at all (Fuller and Young, 2005). The occupancy of the MR in these tissues will be determined by the free rather than total levels of circulating cortisol, which in turn will profoundly vary across the diurnal cycle. In disease states such as hyperaldosteronism or disease models such as the DOC/salt model (Rickard et al., 2009), the tonicaly high levels of mineralocorticoid across the day will result in inappropriate activation of the MR with adverse consequences.

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4. Ligand specificity for the MR In our studies, we have focused on the issue of the specificity of the two physiological ligands, aldosterone and cortisol for the MR in the absence of HSD2. In the context of sodium transport, absence of HSD2, be it in the syndrome of Apparent Mineralocorticoid Excess, an autosomal recessive condition associated with early onset of severe hypertension resulting from mutations in the HSD2 gene; or treatment with agents such as glycyrrhetinic acid, the active ingredient of liquorice, which block HSD2; the effects of cortisol and aldosterone appear largely equivalent. This is not true for other non-epithelial tissue such as neurons and cardiomyocytes where HSD2 protection is absent and cortisol can bind the MR and antagonise the effects of aldosterone (Gomez-Sanchez et al., 1990; Mihailidou, 2006; Sato and Funder, 1996). We have sought to characterise the basis of this ligand discrimination by examining interactions for the MR in which the response to aldosterone and cortisol is not equivalent. Our studies have focused on 3 interactions, those of: ligand-binding mediated transactivation; the interaction of the N-terminus with the LBD and the interaction of the MR with co-regulatory molecules.

5. Mechanisms of ligand binding specificity Given that cortisol binds both to the MR and the GR, yet aldosterone has a very low affinity for the GR, some years ago we elected to dissect the structural basis of this distinction using a chimeric approach (Rogerson et al., 1999, 2007). Sixteen MR/GR LBD chimeras were created using 3 break points at identical positions in the MR and GR LBD (Rogerson et al., 1999). These points were chosen prior to the publication of the crystal structures for the GR (Bledsoe et al., 2002) and MR (Bledsoe et al., 2005; Fagart et al., 2005; Li et al., 2005) LBD; they were chosen on the basis of areas of sequence identity on the assumption that the canonical structure of the LBD was less likely to be disturbed, indeed that supposition was correct in that all LBD chimeras bound ligand, albeit with somewhat variable affinities. Using both binding and transactivation assays, we found that both aldosterone binding and transactivation required that the second segment was MR sequence whereas for cortisolmediated transactivation c.f. binding, the second and fourth regions needed to be either derived from the MR or the GR. Thus, although not the focus of the study, we identified a clear distinction between the nature of the agonist interactions of the two ligands. Subsequently (Rogerson et al., 2007) a series of further subchimeras were created in the second segment (amino acids 804– 870 of the MR). This identified a region of 25 amino acids (MR 820– 844) that if substituted into the equivalent region in the GR, conferred high affinity aldosterone binding on the GR. Of these 25 amino acids, 9 were conserved between the MR and the GR. Further analysis using site-directed mutagenesis led to the conclusion that 4 distinct clusters or single amino acids were required to confer specificity. This finding was consistent with other similar chimeric studies between the AR and the PR (Vivat et al., 1997), the GR and the PR (Robin-Jagerschmidt et al., 2000) and also the MR and the GR (Martinez et al., 2005) where the regions identified, although less resolved, overlapped with the MR 820–844 region. Of the amino acids in this region only one, the phenylalanine at position 829 in the MR, contributes to the ligand-binding pocket of the MR LBD (Bledsoe et al., 2005); however this residue is also found in the GR, arguing that it is not involved in conferring specificity; indeed it appears that the mechanism of the specificity is not conferred by direct interaction with the ligand. Amino acids 820–844 of the MR correspond to the C-terminal of helix 5, the N-terminus of helix 6 and the loop between, a region that sits largely on the surface of the LBD, which led us to conclude that the differences in affinity were probably conferred by changes in confirmation induced by the

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interaction of the unliganded receptor with the hsp-90 complex (Bruner et al., 1997). In this context, a recent study by Shibata et al. (2013) explored the role of phosphorylation in MR action. They identified serine 843 as being a critical residue in MR action in that phosphorylation of this serine rendered the MR inactive. Further they suggested that this mechanism was pivotal in dissociating the effects of MR activation on sodium and potassium transport. They argued that high potassium induced phosphorylation of the MR in renal intercalated cells, a phosphorylation event reversed by angiotensin II treatment, whereas this pathway was not operative in the principal cells which are primarily involved in the sodium flux. Phosphorylation of serine 843 prevents aldosterone binding; that it sits within the 820–844 region is consistent with the pivotal role this region plays in defining ligand affinity. 6. Interdomain interactions Although the work of Green and Chambon (1987) demonstrated rather elegantly the modular nature of the principal domains of the steroid receptors; it subsequently became clear particularly, from studies of the AR (Langley et al., 1995; Zhou et al., 1995) that in an interaction between the N-terminus and the LBD, the N/C-interaction was fundamental to AR function. This was reinforced by the finding that mutations which cause androgen insensitivity syndrome have been identified to selectively abrogate the N/C-interaction in the human androgen receptor (Thompson et al., 2001). An N/C-interaction has also been described for the progesterone receptor (Tetel et al., 1999) and estrogen receptor α (Metivier et al., 2001). We identified an equivalent interaction for the MR but not the GR (Rogerson and Fuller, 2003). This aldosterone-dependent interaction was demonstrated using the mammalian 2-hybrid assay under identical conditions to those used to establish the interaction for the AR. The interaction is aldosteronedependent and an intact AF-2 function is not an absolute requirement, consistent with the notion that the interaction does not, in contrast to the AR, involve an LxxLL, or similar, motif. The MR interaction is antagonised by spironolactone and eplerenone, and is conserved across evolution in that we were able to demonstrate this interaction using the zebra fish MR (Pippal et al., 2011). Somewhat to our surprise, for the human MR, cortisol and deoxycorticosterone are unable to mediate the interaction and indeed antagonised the aldosterone-induced interaction (Pippal et al., 2009). This represents a striking discrimination of aldosterone and cortisol binding at the MR. Since the basis of the N/C-interaction is a protein–protein interaction, it provides compelling evidence that the confirmation induced by the 2 ligands is different. We have also demonstrated that the interaction is a direct interaction; however the exact structural basis of the interaction has proven somewhat elusive. A series of truncations and deletions of the N-terminus has been difficult to interpret presumably due to the unstructured nature of the N-terminal domain, with several regions appearing to contribute to the interaction (Pippal et al., 2009). Recent unpublished data suggest that surface residues in helix 11 of the LBD may play a critical role in mediating interaction. It is tempting to speculate that this interaction, although arguably irrelevant in the renal MRmediated response, where cortisol and aldosterone appear equivalent in the absence of HSD2, may play a critical role in those tissues where cortisol acts as an antagonist. Given that such observations are largely in vitro observations, it is likely that this distinction can only be fully elucidated using an in vivo model. The possibility that an understanding of this mechanism may provide novel therapeutic opportunities remains enticing. 7. MR co-regulators Our third strategy to identify ligand discriminant differences at the MR has been to explore the role of co-regulator interactions

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looking for ligand-specificity. Although a number of the known MR coactivators have been characterised primarily in the context of other steroid receptors, there have been a series of studies seeking to identify MR-specific coactivators. In these studies the focus generally has been on the N-terminus as a way of identifying interactions which are likely to be specific to the MR. These studies have not therefore addressed the issue of ligand-specificity and not unsurprisingly have failed to identify ligand-specificity. Of the MR co-regulators described (reviewed by Yang and Fuller, 2012), none have been identified which show ligand discrimination. Two studies which explored interactions between known coactivator-derived LxxLL motifs in the MR LBD using a mammalian 2-hybrid assay (Hultman et al., 2005) or an alpha-screen (Li et al., 2005) found not only a relatively small number of interactions but also that all interactions were seen in the presence of both cortisol and aldosterone. Yang et al. (2011) have used LxxLL constrained phage display with full-length MR (Clyne et al., 2009) to identify a range of MRinteracting peptides; however ligand-specificity was not observed. In order to address this question, we have recently published a study based on a yeast 2-hybrid (Y-2-H) screen with the MR LBD in which we screened for ligand discriminant interactions (Rogerson et al., 2014). Although the majority of interactions identified were seen with both aldosterone and cortisol, and indeed several represented known coactivators, including well characterised relatively generic coactivators such as SRC-1 and PGC-1α, we did identify several Y-2-H clones which appeared to be ligand discriminant. We have fully characterised one of these which encodes tesmin. Although this aldosterone-specific clone showed absolute specificity in the Y-2-H assay, when the cDNA fragment was subcloned for analysis in an M-2-H assay, an interaction was observed with the MR LBD in the presence of both aldosterone and cortisol; however the interaction was 12-fold more active for aldosterone than cortisol. The Y-2-H clone encodes a fragment of tesmin or metalothioninelike 5 (MLT5) which is a 508 amino acids long protein with a cysteine rich region that binds zinc. The original clone contains two LxxLL motifs. Tesmin was first identified in the mouse as a testis-specific protein and as a marker of germ cell differentiation; however expression tags for tesmin are found in a wide range of tissues. When full length tesmin was analysed in a transactivation assay, it was found to coactivate aldosterone-induced MR-mediated transactivation but not cortisol-induced MR-mediated transactivation. It was also able to coactivate deoxycorticosterone-induced transactivation and the interaction was antagonised by spironolactone. This same ligand-specific coactivation was seen not only at the MMTV promoter but also for several other artificial and natural MR-regulated promoters. Tesmin and MR were coimmunoprecipitated in the presence of aldosterone but not cortisol arguing for a direct interaction; indeed inactivation of the AF-2 region in the LBD inhibited the interaction, again consistent with a direct LxxLL-mediated interaction. This was further confirmed by mutation of the two LxxLL motifs by replacement of the last two leucines by alanine residues. In the presence of these two mutations, co-immunoprecipitation was no longer observed. Similarly transactivation was compromised and indeed inhibited by these mutations. A second isoform of tesmin which is C-terminal truncated but contains the LxxLL motifs was also active as a coactivator. The actual structural determinants of the coactivation per se remain to be determined although clearly the LxxLL motifs are essential for the primary interaction. The structural basis of the ligand discrimination also remains to be determined. 8. Conclusions The above studies clearly demonstrate that the interactions of aldosterone and cortisol with the MR are not equivalent in that each has different binding determinants and induces a distinct

conformation in the LBD of the MR. That the induced confirmation is subtly different is clearly the basis of the differences in the interactions observed, be that with the N-terminus or indeed with coregulatory molecules. The physiological significance of this distinction remains to be determined but previous experiments demonstrating differences including the ability of cortisol to antagonise aldosterone in specific tissues argues that this is relevant and indeed a potentially important observation. The current MR antagonists, be they the steroidal agents spironolactone and eplerenone or new and emerging non-steroidal compounds (Fagart et al., 2010), all appear to equivalently antagonise the MR in both epithelial tissues and non-epithelial tissues. Whilst MR antagonism in the cardiovascular tissues is clearly the desired therapeutic endpoint (Zannad et al., 2010), antagonism of the physiological response in the sodium transporting epithelia is confounded by the associated potassium retention with consequent hyperkalaemia (Juurlink et al., 2004), the major limitation to a more extensive use of what is otherwise a very potent intervention. It is appealing to think that selective MR modulators may be developed with a preponderance of cardiovascular over renal effects. Understanding the nature of the interactions of the MR, particularly with respect to ligand-discrimination, may be an important precursor to the rational design of such potential novel therapeutics.

Acknowledgements The author wishes to thank Claudette Thiedeman for preparation of the manuscript. This work was supported by National Health and Medical Research Council through Project Grants (#1002575, #1058336) and a Senior Principal Research Fellowship (#1002559). MIMR-PHI is supported by the Victorian Government’s Operational Infrastructure Scheme.

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