ESRRA (estrogen-related receptor alpha)

	Schematic of nuclear receptor structure and function. ERRa is a member of the nuclear receptor (NR) superfamily of transcription factors and is most closely related to estrogen receptor alpha (ERa). The modular structure of NRs consists of seven (A-F) domains. The A/B region, which harbors activation function 1 (AF-1), is not well-conserved across NRs, but regions C and E are highly conserved and harbor, respectively, the DNA-binding domain (DBD) and ligand-binding domain (LBD). ERRa shares with ERa 68% sequence identity within the DBD and 33% within the LBD. The functional regions of the DBD have been finely mapped. In addition to two zinc finger motifs, this domain contains a Proximal-box (P-box) which determines DNA sequence specificity, and a Dimerization-box (D-box), which part of the dimerization interface.
Description	ERRa is a 45.5 kDa, 423 amino acid orphan nuclear receptor. Although closely related to the estrogen receptors, its transcriptional activity is regulated to any significant degree by estrogens. ERRa binds to specific DNA sequences within target gene promoters as a monomer or homodimer and recruits coactivating proteins, the best known of which is PGC-1a.
Expression	ERRa is ubiquitously expressed throughout development with the highest levels of expression in tissues that oxidize fatty acids such as kidney, heart, cerebellum, intestine and skeletal muscle (nursa).
Localisation	ERRa is thought to be predominately nuclear, although recently it has been reported to be perinuclear and cytoplasmic in breast cancer tissue (Jarzabek et al., 2009).
Function	The function of ERRa as a metabolic regulator is supported by the observation that erra-null mice demonstrate impaired fat metabolism and absorption (Luo et al., 2003). It has recently been demonstrated that erra-null mice also have a reduced capacity for adaptation to hemodynamic stressors. Due to this functional deficit, these mice often develop cardiac contractile dysfunction. The cardiac remodeling under stress in ERR-null mice is due to defects in ATP synthesis and reduced phosphocreatine stores, which are both characteristic of pathologic cardiac hypertrophy (Huss et al., 2007). That the expression of ERRa is elevated in exercising muscle and in fasting liver specifically implicates this receptor in beta-oxidation of fatty acids, a metabolic pathway that is highly active under these conditions. On a mechanistic level, several studies have revealed that ERRa is involved in the transcriptional regulation of genes required for mitochondrial biogenesis, oxidative phosphorylation and fatty acid oxidation (Huss et al., 2004; Mootha et al., 2004; Dufour et al., 2007). Thus far, metabolic studies of ERRa function have mainly focused on its role as the downstream effector of PGC-1a. PGC-1a is a promiscuous nuclear receptor coactivator expressed at low basal levels but induced by fasting and other metabolic stresses (Puigserver and Spiegelman, 2003). PGC-1beta, a related cofactor, may have similar functions, although its expression level is not as acutely regulated by variations in energy demand (Yoon et al., 2001). Rather than being regulated by ligand, the magnitude of ERRa activity is thought to be largely dependent on the presence of transcriptional coactivators such as PGC-1a and beta. Interest in the ERR-PGC-1 regulatory axis was heightened by the observation that there is a decrease in both PGC-1a and PGC-1beta in the skeletal muscle of patients with diabetes and obesity (Mootha et al., 2003).
Homology	Sequence analysis reveals that the ERRs and the classical estrogen receptors share a high degree of homology within their DNA and ligand binding domains. In particular, ERRa shares with ERa approximately 68% sequence identity within the DNA binding domain and 33% within the ligand binding domains. This relationship provides a structural basis both for the conserved nature of DNA binding and the divergence in hormone binding between these two receptors.

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