Note | The domain structure of ERRgamma is typical for a member of the nuclear receptor superfamily. ERRgamma and its family members (ERRalpha and ERRbeta) are most similar to the classical estrogen receptors alpha and beta (ERalpha, ERbeta). |
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| Schematic of ERRgamma domain structure. aa = amino acid, and numbers correspond to the ERRgamma1 isoform; AF1 = activation function-1 ; DBD = DNA binding domain ; LBD = ligand binding domain; (%) denotes amino acid identity to estrogen receptor alpha (ERalpha). |
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Description | AF1: Like most nuclear receptors, the activation function -1 (AF1) domain of ERRgamma participates in the regulation of transcription by the receptor. It is the region to which several coactivators can bind (see below), as well as the site of post-translational modification. Phosphorylation of the family member ERRalpha at serine 19 has recently been shown to direct subsequent SUMOylation at a nearby lysine (residue 14), and that this series of post-translational modifications is in fact inhibitory for receptor transcriptional activity (Vu et al., 2007). While ERRgamma lacks a serine residue in this position, in March of 2008 Tremblay et al. confirmed ERRalpha phosphorylation at serine 19 and reported that ERRgamma transcriptional activity can also be inhibited by SUMOylation of lysine 40 that is directed by phosphorylation of serine 45 (Tremblay et al., 2008). The authors went on to identify protein inhibitor of activated signal transducer and activator of transcription gamma (PIAS4) as a functional E3 ligase for the family member ERRalpha, and hypothesized that PIAS4 and the SUMO-conjugating enzyme Ubc9 are responsible for the modification of ERRgamma as well. DBD: The greater than 60% identity between the DNA binding domains (DBDs) of ERRgamma and ERalpha (see figure) results in ERRgamma being able to bind the estrogen response element (ERE: AGGTCA...TGACCT). However, ERRgamma also binds to what was originally identified as the consensus sequence for steroidogenic factor 1 (SF1, SFRE: TCAAGGTCA) (Horard and Vanacker, 2003). LBD: A key difference between ERRgamma and most members of the nuclear receptor superfamily is the regulation of its transcriptional activity. There is only about 23% sequence identity between classical ERalpha and ERRgamma in the ligand binding domain (LBD) (see figure). Therefore, while ERalpha (like most nuclear receptors) is dependent upon ligand for full activation, ERRgamma and the other members of the ERR family exhibit constitutive transcriptional activity. None of the ERR family members are affected by estradiol (E2) stimulation because their LBDs cannot accommodate E2 binding (discussed in Ariazi and Jordan, 2006). However, ERRgamma transcriptional activity at EREs and SFREs can be inhibited by 4-hydroxytamoxifen (4HT) and the synthetic estrogen diethylstilbestrol (Greschik et al., 2002; Greschik et al., 2004; Yu and Forman, 2005). In contrast, 4HT-bound ERRgamma acquires the ability to positively regulate transcription at activator protein-1 (AP1) sites (Huppunen et al., 2004), but the mechanism by which this occurs is not clear. ERRgamma constitutive activity can be enhanced or stabilized by the synthetic agonist GSK4716 (Yu and Forman, 2005; Zuercher et al., 2005), the endocrine disruptor Bisphenol A (BPA) (Matsushima et al., 2007; Takayanagi et al., 2006), and a variant of this compound (4-alpha-cumylphenol) (Matsushima et al., 2008). ERRgamma constitutive activity has also recently been shown to be inhibited by kaempferol, a dietary flavonoid (Wang et al., 2009). Coactivators/Corepressors: Like other nuclear receptors, ERRgamma transcriptional activity is modulated by binding to other proteins that can serve as coactivators or corepressors. Coactivators and corepressors bind directly to nuclear receptors, most often within the carboxyl-terminal activation function-2 (AF2) domain that participates in ligand-binding but some can exert their effects by binding to the amino-terminal AF1 domain or the flexible hinge region of the receptor (Hall and McDonnell, 2005). Among the coactivators that have been demonstrated to bind and activate ERRgamma are PPARGC1A (also known as PGC-1alpha), TLE1, NCOA1, NCOA2 and, under certain circumstances, NRIP1 (Gowda et al., 2006; Sanyal et al., 2004). PPARGC1A is best known as a coactivator for peroxisome proliferator-activated receptor gamma, but it is also able to enhance ERRgamma activity in an AF1-dependent manner (Hentschke et al., 2002). TLE1 can also enhance ERRgamma activity by binding to its AF1 domain, and the coactivator function of TLE1 in this context is unique because this protein typically functions as a repressor for Drosophila and mammalian high mobility group (HMG) box transcription factors. TLE1 also has no known interactions with classical ERalpha or any other nuclear receptor (Hentschke and Borgmeyer, 2003). In contrast, NCOA1 and NCOA2 are well-known AF2-dependent coactivators of ERalpha and other nuclear receptors, including ERRgamma (reviewed in Hall and McDonnell, 2005). |
Expression | In fetal and adult human tissues, ERRgamma1 and ERRgamma2 are most highly expressed in the heart, brain, kidney, and skeletal muscle (Heard et al., 2000), while ERRgamma3 expression appears to be restricted to the prostate and adipose tissue (Kojo et al., 2006). Interestingly, in the mouse ERRgamma is also expressed in these tissues but is even more abundant in the brain stem and spinal cord (http://www.nursa.org/10.1621/datasets.02001). |
Localisation | Endogenous ERRgamma is localized to the nucleus in human breast cancer (Park et al., 2005) and prostate tissue (Yu et al., 2007), and transfected, exogenous ERRgamma is also found in the nucleus of tissue culture cells (Yasumoto et al., 2007). |
Function | Molecular function: transcription factor activity, steroid hormone receptor activity, steroid binding, protein binding, zinc ion binding. Biological processes: transcription, positive regulation of transcription (DNA-dependent).. As a member of the nuclear receptor superfamily, ERRgamma is a transcription factor. In the mouse, homozygous knockout of ERR results in death on or about postnatal day 1 caused by severe cardiac defects (Alaynick et al., 2007). This is due to a key metabolic defect whereby the animals are unable to switch from deriving energy from carbohydrates in utero to lipids as a neonate because ERRgamma controls the transcription of essential genes that regulate oxidative metabolic processes (Giguere, 2008). |
Homology | ERRgamma is highly conserved among several species. At the amino acid level, human ERRgamma is 100% identical to rat, mouse, and cow ERRgamma, and 99.78% identical to dog and chimpanzee ERRgamma. |
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