Liver X receptor beta explained

Liver X receptor beta (LXR-β) is a member of the nuclear receptor family of transcription factors. LXR-β is encoded by the gene (nuclear receptor subfamily 1, group H, member 2).^[1]

Function

The liver X receptors (LXRs) were originally identified as orphan members of the nuclear receptor superfamily because their ligands were unknown. Like other receptors in the family, LXRs heterodimerize with retinoid X receptor and bind to specific response elements (LXREs) characterized by direct repeats separated by 4 nucleotides. Two genes, alpha (LXRA) and beta, are known to encode LXR proteins.^{[1] [2]}

Structure

Crystal structure of human liver X receptor β(LXRβ) forming heterodimer with its partner retinoid X receptor α(RXRα) on its cognate element, an AGGTCA direct repeat spaced by 4 nt shows an extended X-shaped arrangement, with DNA- and ligand-binding domains crossed. The LXRβ core binds DNA via canonical contacts and auxiliary DNA contacts that enhance affinity for the response element.^[3]

Interactions

Liver X receptor beta has been shown to interact with NCOA6^[4] and Retinoid X receptor alpha.^[5]

Further reading

• Seol W, Choi HS, Moore DD . Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors . Molecular Endocrinology . 9 . 1 . 72–85 . Jan 1995 . 7760852 . 10.1210/mend.9.1.7760852 . free .
• Le Beau MM, Song C, Davis EM, Hiipakka RA, Kokontis JM, Liao S . Assignment of the human ubiquitous receptor gene (UNR) to 19q13.3 using fluorescence in situ hybridization . Genomics . 26 . 1 . 166–8 . Mar 1995 . 7782080 . 10.1016/0888-7543(95)80100-Z .
• Shinar DM, Endo N, Rutledge SJ, Vogel R, Rodan GA, Schmidt A . NER, a new member of the gene family encoding the human steroid hormone nuclear receptor . Gene . 147 . 2 . 273–6 . Sep 1994 . 7926814 . 10.1016/0378-1119(94)90080-9 .
• Song C, Kokontis JM, Hiipakka RA, Liao S . Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors . Proceedings of the National Academy of Sciences of the United States of America . 91 . 23 . 10809–13 . Nov 1994 . 7971966 . 45115 . 10.1073/pnas.91.23.10809 . 1994PNAS...9110809S . free .
• Janowski BA, Grogan MJ, Jones SA, Wisely GB, Kliewer SA, Corey EJ, Mangelsdorf DJ . Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta . Proceedings of the National Academy of Sciences of the United States of America . 96 . 1 . 266–71 . Jan 1999 . 9874807 . 15128 . 10.1073/pnas.96.1.266 . 1999PNAS...96..266J . free .
• Feltkamp D, Wiebel FF, Alberti S, Gustafsson JA . Identification of a novel DNA binding site for nuclear orphan receptor OR1 . The Journal of Biological Chemistry . 274 . 15 . 10421–9 . Apr 1999 . 10187832 . 10.1074/jbc.274.15.10421 . free .
• Lee SK, Jung SY, Kim YS, Na SY, Lee YC, Lee JW . Two distinct nuclear receptor-interaction domains and CREB-binding protein-dependent transactivation function of activating signal cointegrator-2 . Molecular Endocrinology . 15 . 2 . 241–54 . Feb 2001 . 11158331 . 10.1210/mend.15.2.0595 . free .
• Whitney KD, Watson MA, Goodwin B, Galardi CM, Maglich JM, Wilson JG, Willson TM, Collins JL, Kliewer SA . Liver X receptor (LXR) regulation of the LXRalpha gene in human macrophages . The Journal of Biological Chemistry . 276 . 47 . 43509–15 . Nov 2001 . 11546778 . 10.1074/jbc.M106155200 . free .
• Whitney KD, Watson MA, Collins JL, Benson WG, Stone TM, Numerick MJ, Tippin TK, Wilson JG, Winegar DA, Kliewer SA . Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system . Molecular Endocrinology . 16 . 6 . 1378–85 . Jun 2002 . 12040022 . 10.1210/mend.16.6.0835 . free .
• Brendel C, Schoonjans K, Botrugno OA, Treuter E, Auwerx J . The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity . Molecular Endocrinology . 16 . 9 . 2065–76 . Sep 2002 . 12198243 . 10.1210/me.2001-0194 . free .
• Mo J, Fang SJ, Chen W, Blobe GC . Regulation of ALK-1 signaling by the nuclear receptor LXRbeta . The Journal of Biological Chemistry . 277 . 52 . 50788–94 . Dec 2002 . 12393874 . 10.1074/jbc.M210376200 . free .
• Williams S, Bledsoe RK, Collins JL, Boggs S, Lambert MH, Miller AB, Moore J, McKee DD, Moore L, Nichols J, Parks D, Watson M, Wisely B, Willson TM . X-ray crystal structure of the liver X receptor beta ligand binding domain: regulation by a histidine-tryptophan switch . The Journal of Biological Chemistry . 278 . 29 . 27138–43 . Jul 2003 . 12736258 . 10.1074/jbc.M302260200 . free .
• Färnegårdh M, Bonn T, Sun S, Ljunggren J, Ahola H, Wilhelmsson A, Gustafsson JA, Carlquist M . The three-dimensional structure of the liver X receptor beta reveals a flexible ligand-binding pocket that can accommodate fundamentally different ligands . The Journal of Biological Chemistry . 278 . 40 . 38821–8 . Oct 2003 . 12819202 . 10.1074/jbc.M304842200 . free .
• Fukuchi J, Song C, Ko AL, Liao S . Transcriptional regulation of farnesyl pyrophosphate synthase by liver X receptors . Steroids . 68 . 7–8 . 685–91 . Sep 2003 . 12957674 . 10.1016/S0039-128X(03)00100-4 . 6023862 .
• Hoerer S, Schmid A, Heckel A, Budzinski RM, Nar H . Crystal structure of the human liver X receptor beta ligand-binding domain in complex with a synthetic agonist . Journal of Molecular Biology . 334 . 5 . 853–61 . Dec 2003 . 14643652 . 10.1016/j.jmb.2003.10.033 .
• Walczak R, Joseph SB, Laffitte BA, Castrillo A, Pei L, Tontonoz P . Transcription of the vascular endothelial growth factor gene in macrophages is regulated by liver X receptors . The Journal of Biological Chemistry . 279 . 11 . 9905–11 . Mar 2004 . 14699103 . 10.1074/jbc.M310587200 . free .

Notes and References

1. Web site: Entrez Gene: NR1H2 nuclear receptor subfamily 1, group H, member 2.
2. Song C, Hiipakka RA, Kokontis JM, Liao S . Ubiquitous receptor: structures, immunocytochemical localization, and modulation of gene activation by receptors for retinoic acids and thyroid hormones . Annals of the New York Academy of Sciences . 761 . 2. 38–49 . Jun 1995 . 7625741 . 10.1111/j.1749-6632.1995.tb31367.x . 1995NYASA.761...38S . 27208069 .
3. Lou X, Toresson G, Benod C, Suh JH, Philips KJ, Webb P, Gustafsson JA . Structure of the retinoid X receptor α-liver X receptor β (RXRα-LXRβ) heterodimer on DNA . Nature Structural & Molecular Biology . 21 . 3 . 277–81 . Mar 2014 . 24561505 . 10.1038/nsmb.2778 . 23226682 .
4. Lee SK, Jung SY, Kim YS, Na SY, Lee YC, Lee JW . Two distinct nuclear receptor-interaction domains and CREB-binding protein-dependent transactivation function of activating signal cointegrator-2 . Molecular Endocrinology . 15 . 2 . 241–54 . Feb 2001 . 11158331 . 10.1210/mend.15.2.0595 . free .
5. Seol W, Choi HS, Moore DD . Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors . Molecular Endocrinology . 9 . 1 . 72–85 . Jan 1995 . 7760852 . 10.1210/mend.9.1.7760852 . free .