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Review
, 184, 11-19

NR3E Receptors in Cnidarians: A New Family of Steroid Receptor Relatives Extends the Possible Mechanisms for Ligand Binding

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Review

NR3E Receptors in Cnidarians: A New Family of Steroid Receptor Relatives Extends the Possible Mechanisms for Ligand Binding

Konstantin Khalturin et al. J Steroid Biochem Mol Biol.

Abstract

Steroid hormone receptors are important regulators of development and physiology in bilaterian animals, but the role of steroid signaling in cnidarians has been contentious. Cnidarians produce steroids, including A-ring aromatic steroids with a side-chain, but these are probably made through pathways different than the one used by vertebrates to make their A-ring aromatic steroids. Here we present comparative genomic analyses indicating the presence of a previously undescribed nuclear receptor family within medusozoan cnidarians, that we propose to call NR3E. This family predates the diversification of ERR/ER/SR in bilaterians, indicating that the first NR3 evolved in the common ancestor of the placozoan and cnidarian-bilaterian with lineage-specific loss in the anthozoans, even though multiple species in this lineage have been shown to produce aromatic steroids, whose function remain unclear. We discovered serendipitously that a cytoplasmic factor within epidermal cells of transgenic Hydra vulgaris can trigger the nuclear translocation of heterologously expressed human ERα. This led us to hypothesize that aromatic steroids may also be present in the medusozoan cnidarian lineage, which includes Hydra, and may explain the translocation of human ERα. Docking experiments with paraestrol A, a cnidarian A-ring aromatic steroid, into the ligand-binding pocket of Hydra NR3E indicates that, if an aromatic steroid is indeed the true ligand, which remains to be demonstrated, it would bind to the pocket through a partially distinct mechanism from the manner in which estradiol binds to vertebrate ER.

Keywords: A-ring aromatic steroid; Aromatization; Cnidarian; Steroid receptor.

Figures

Figure 1.
Figure 1.. A model for A-ring aromatic steroid synthesis pathway in the octocoral cnidarian Dendronephthya studeri, based on the molecules described in Yan et al., 2011, and the knowledge of enzymatic pathways known from other organisms.
(1): Cholesta-1,4,22-trien-3-one; (2): (22E)-19-Norcholesta-1,3,5(10),22-tetraen-3-ol; (3): 24-Methylenecholesta-1,4,22-trien-3-one; (4): 24-Methylene-19-norcholesta-1,3,5(10),22-tetraen-3-ol. Paraestrol A (19-norcholesta-1,3,5(10)-trien-3-ol) has been proposed as an ancestral steroid [28]. We have named « dienone aromatization » the proposed aromatization reaction to stress the difference from the vertebrate case where there is no delta1–2 double bond (highlighted in yellow) on the A ring.
Figure 2.
Figure 2.. A new NR3E family at the base of the bilaterian ER/ERR/SR clade.
The tree was calculated using maximum-likelihood. Likelihood ratio test branch support values upper than 0.70 are indicated. Bilaterian sequences are shown in blue and cnidarian sequences in brown. The Hydra NR3E is highlighted in red. Mollusc and annelid NR3Ds correspond to proteins that were previously labelled as ERs [46], Similar analyses using the LBD alone gave largely similar results and did not affect the placement of the cnidarian nuclear receptors.
Figure 3.
Figure 3.. An endogenous cytoplasmic factor induces hERα-GFP translocation from cytoplasm to nucleus in Hydra epithelial cells.
a) Schematic representation of transgenic constructs with GFP only and with human ERα-GFP driven by 1.4 kb of Hydra ß-actin promoter, b) One week old Hydra embryo injected with the control construct. GFP positive blastomeres are visible, c) Hydra embryo injected with actin::ERα-GFP construct. Several GFP positive nuclei are visible and the cytoplasm of blastomeres is not GFP positive, d) Head of transgenic Hydra polyp, e) Body column of a transgenic polyp. Green spots are the nuclei of ectodermal epithelia cells which are filled with hERα-GFP without addition of any ligand.
Figure 4.
Figure 4.. Paraestrol A docking into the ligand binding pocket of an estrogen receptor a homology-based model of Hydra NR3E.
(a) Superposition of the NR3E structural model using ERα structure (in violet) where the paraestrol A is represented in pink, the ERα structure used as template (PDB id: 1ERE) is represented in cyan and the 17β-estradiol in blue, (b) Detailed view of the binding pocket of the NR3E ERα-based model, highlighting interactions (in yellow dashed lines) between the paraestrol and residues Q42 and N79. W80 involved in the cnidarian-specific π-π interaction is also shown, (c) Detailed view of the binding pocket of ERα, highlighting interactions (in yellow dashed lines) between the 17β-estradiol and residues E353, R394 and H524 (corresponding to V201 in NR3E model).
Figure 5.
Figure 5.. Alignment of H3, H4-H5 and H10-H11 helices in the NR3 family, compared to NR3E from Hydra.
Residues involved in estrogen binding in ER are highlighted in green. Homologous residues that are shared by the cnidarian NR3E and the vertebrate oxosteroid receptors (SRs) are highlighted in pink. The cnidarian-specific N79-W80 anchor is highlighted in brown. An alignment for the entire DNA-binding domain and ligand-binding domain is shown in Supplemental Figure 2. The helices from the ligand-binding domain are mapped according to the structure of human ERα [48], Calculations of identity percentages for both domains are also provided in Supplemental Table1.
Figure 6.
Figure 6.. A possible pathway for steroid enterocrine signaling in cnidarians.
Steroids, in green, could be produced from dietary sterols in the gut (in yellow) and go to the gonad (in orange) along with other nutrients. Gonads may be of ectodermal or endodermal origin, depending on the species. The pink tissue represents the mesoglea, which consists of a gelatinous matrix that contains collagen fibers and usually some cells. The mesoglea forms a hydrostatic skeleton, but does not contain a circulating body fluid or play a known role in circulation.

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