Small heterodimer partner explained

The small heterodimer partner (SHP) also known as NR0B2 (nuclear receptor subfamily 0, group B, member 2) is a protein that in humans is encoded by the NR0B2 gene.^[1] SHP is a member of the nuclear receptor family of intracellular transcription factors.^[2] SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain. Therefore, it is technically neither a transcription factor nor nuclear receptor but nevertheless it is still classified as such due to relatively high sequence homology with other nuclear receptor family members.

Function

The principal role of SHP appears to be repression of other nuclear receptors through association to produce a non-productive heterodimer.^[3] The protein has also been identified as a mediating factor in the metabolic circadian clock.^[4] Research shows that it interacts with retinoid and thyroid hormone receptors, inhibiting their ligand-dependent transcriptional activation. In addition, interaction with estrogen receptors has been demonstrated, leading to inhibition of function. Studies suggest that the protein represses nuclear hormone receptor-mediated transactivation via two separate steps: competition with coactivators and the direct effects of its transcriptional repressor function.^[1]

Structure and ligands

A crystal structure of the LBD-only SHP, generated by co-crystallisation with EID1, has been obtained. Instead binding to the usual AF-2 site, EID1 fills in the place of what is usually helix α1 of an LBD and makes SHP more soluble. The overall structure resembles the apo (ligandless) form of other LBDs. Some synthetic retinoid ligands can bind to SHP's LBD and promote its interaction with LXXLL-containing corepressors using the AF-2 site.

Interactions

Large and medium scale Y2H experiments as well as text mining of the NR literature have highlighted the important role of SHP in the Nuclear Receptor dimerization network and its relatively highly connected status, compared to other NRs.^[5]

Small heterodimer partner has been shown to interact with:

• Androgen receptor,^[6]
• Estrogen receptor alpha,^[7]
• Hepatocyte nuclear factor 4 alpha,^[8]
• Liver receptor homolog-1,^[9]
• Liver X receptor alpha,^[10]
• Peroxisome proliferator-activated receptor gamma,^[11]
• Retinoic acid receptor alpha,^{[12] [13]}
• EID1,^[14]
• Retinoid X receptor alpha.^{[8] [10]}

Further reading

• Seol W, Choi HS, Moore DD . An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors . Science . 272 . 5266 . 1336–9 . May 1996 . 8650544 . 10.1126/science.272.5266.1336 . 1996Sci...272.1336S . 32853062 .
• Seol W, Hanstein B, Brown M, Moore DD . Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner) . Molecular Endocrinology . 12 . 10 . 1551–7 . October 1998 . 9773978 . 10.1210/me.12.10.1551 . free .
• Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD . The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression . Molecular and Cellular Biology . 20 . 1 . 187–95 . January 2000 . 10594021 . 85074 . 10.1128/MCB.20.1.187-195.2000 .
• Johansson L, Båvner A, Thomsen JS, Färnegårdh M, Gustafsson JA, Treuter E . The orphan nuclear receptor SHP utilizes conserved LXXLL-related motifs for interactions with ligand-activated estrogen receptors . Molecular and Cellular Biology . 20 . 4 . 1124–33 . February 2000 . 10648597 . 85230 . 10.1128/MCB.20.4.1124-1133.2000 .
• Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ . Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors . Molecular Cell . 6 . 3 . 507–15 . September 2000 . 11030331 . 10.1016/S1097-2765(00)00050-2 . free .
• Nishigori H, Tomura H, Tonooka N, Kanamori M, Yamada S, Sho K, Inoue I, Kikuchi N, Onigata K, Kojima I, Kohama T, Yamagata K, Yang Q, Matsuzawa Y, Miki T, Seino S, Kim MY, Choi HS, Lee YK, Moore DD, Takeda J . 6 . Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects . Proceedings of the National Academy of Sciences of the United States of America . 98 . 2 . 575–80 . January 2001 . 11136233 . 14629 . 10.1073/pnas.021544398 . free .
• Lee YK, Moore DD . Dual mechanisms for repression of the monomeric orphan receptor liver receptor homologous protein-1 by the orphan small heterodimer partner . The Journal of Biological Chemistry . 277 . 4 . 2463–7 . January 2002 . 11668176 . 10.1074/jbc.M105161200 . free .
• Nishizawa H, Yamagata K, Shimomura I, Takahashi M, Kuriyama H, Kishida K, Hotta K, Nagaretani H, Maeda N, Matsuda M, Kihara S, Nakamura T, Nishigori H, Tomura H, Moore DD, Takeda J, Funahashi T, Matsuzawa Y . 6 . Small heterodimer partner, an orphan nuclear receptor, augments peroxisome proliferator-activated receptor gamma transactivation . The Journal of Biological Chemistry . 277 . 2 . 1586–92 . January 2002 . 11696534 . 10.1074/jbc.M104301200 . free .
• Sanyal S, Kim JY, Kim HJ, Takeda J, Lee YK, Moore DD, Choi HS . Differential regulation of the orphan nuclear receptor small heterodimer partner (SHP) gene promoter by orphan nuclear receptor ERR isoforms . The Journal of Biological Chemistry . 277 . 3 . 1739–48 . January 2002 . 11705994 . 10.1074/jbc.M106140200 . free .
• Gobinet J, Auzou G, Nicolas JC, Sultan C, Jalaguier S . Characterization of the interaction between androgen receptor and a new transcriptional inhibitor, SHP . Biochemistry . 40 . 50 . 15369–77 . December 2001 . 11735420 . 10.1021/bi011384o .
• Klinge CM, Jernigan SC, Risinger KE . The agonist activity of tamoxifen is inhibited by the short heterodimer partner orphan nuclear receptor in human endometrial cancer cells . Endocrinology . 143 . 3 . 853–67 . March 2002 . 11861507 . 10.1210/endo.143.3.8676 . free .
• Ogata M, Awaji T, Iwasaki N, Miyazaki S, Bell GI, Iwamoto Y . Nuclear translocation of SHP and visualization of interaction with HNF-4alpha in living cells . Biochemical and Biophysical Research Communications . 292 . 1 . 8–12 . March 2002 . 11890664 . 10.1006/bbrc.2002.6593 .
• Cao H, Hegele RA . Identification of polymorphisms in the human SHP1 gene . Journal of Human Genetics . 47 . 8 . 445–7 . 2002 . 12181644 . 10.1007/s100380200062 . 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 . September 2002 . 12198243 . 10.1210/me.2001-0194 . free .
• Borgius LJ, Steffensen KR, Gustafsson JA, Treuter E . Glucocorticoid signaling is perturbed by the atypical orphan receptor and corepressor SHP . The Journal of Biological Chemistry . 277 . 51 . 49761–6 . December 2002 . 12324453 . 10.1074/jbc.M205641200 . free .
• Hung CC, Farooqi IS, Ong K, Luan J, Keogh JM, Pembrey M, Yeo GS, Dunger D, Wareham NJ, O' Rahilly S . 6 . Contribution of variants in the small heterodimer partner gene to birthweight, adiposity, and insulin levels: mutational analysis and association studies in multiple populations . Diabetes . 52 . 5 . 1288–91 . May 2003 . 12716767 . 10.2337/diabetes.52.5.1288 . free .
• Lai K, Harnish DC, Evans MJ . Estrogen receptor alpha regulates expression of the orphan receptor small heterodimer partner . The Journal of Biological Chemistry . 278 . 38 . 36418–29 . September 2003 . 12842887 . 10.1074/jbc.M303913200 . free .
• Kovacic A, Speed CJ, Simpson ER, Clyne CD . Inhibition of aromatase transcription via promoter II by short heterodimer partner in human preadipocytes . Molecular Endocrinology . 18 . 1 . 252–9 . January 2004 . 14593077 . 10.1210/me.2003-0211 . free .

Notes and References

1. Web site: Entrez Gene: NR0B2 nuclear receptor subfamily 0, group B, member 2.
2. Lee HK, Lee YK, Park SH, Kim YS, Park SH, Lee JW, Kwon HB, Soh J, Moore DD, Choi HS . 6 . Structure and expression of the orphan nuclear receptor SHP gene . The Journal of Biological Chemistry . 273 . 23 . 14398–402 . June 1998 . 9603951 . 10.1074/jbc.273.23.14398 . free .
3. Båvner A, Sanyal S, Gustafsson JA, Treuter E . Transcriptional corepression by SHP: molecular mechanisms and physiological consequences . Trends in Endocrinology and Metabolism . 16 . 10 . 478–88 . December 2005 . 16275121 . 10.1016/j.tem.2005.10.005 . 7884363 .
4. Wu N, Kim KH, Zhou Y, Lee JM, Kettner NM, Mamrosh JL, Choi S, Fu L, Moore DD . 6 . Small Heterodimer Partner (NR0B2) Coordinates Nutrient Signaling and the Circadian Clock in Mice . Molecular Endocrinology . 30 . 9 . 988–95 . September 2016 . 27427832 . 5004116 . 10.1210/me.2015-1295 .
5. Amoutzias GD, Pichler EE, Mian N, De Graaf D, Imsiridou A, Robinson-Rechavi M, Bornberg-Bauer E, Robertson DL, Oliver SG . 6 . A protein interaction atlas for the nuclear receptors: properties and quality of a hub-based dimerisation network . BMC Systems Biology . 1 . 34 . July 2007 . 17672894 . 1971058 . 10.1186/1752-0509-1-34 . free .
6. Gobinet J, Auzou G, Nicolas JC, Sultan C, Jalaguier S . Characterization of the interaction between androgen receptor and a new transcriptional inhibitor, SHP . Biochemistry . 40 . 50 . 15369–77 . December 2001 . 11735420 . 10.1021/bi011384o .
7. Klinge CM, Jernigan SC, Risinger KE . The agonist activity of tamoxifen is inhibited by the short heterodimer partner orphan nuclear receptor in human endometrial cancer cells . Endocrinology . 143 . 3 . 853–67 . March 2002 . 11861507 . 10.1210/endo.143.3.8676 . free .
8. Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD . The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression . Molecular and Cellular Biology . 20 . 1 . 187–95 . January 2000 . 10594021 . 85074 . 10.1128/MCB.20.1.187-195.2000 .
9. Lee YK, Moore DD . Dual mechanisms for repression of the monomeric orphan receptor liver receptor homologous protein-1 by the orphan small heterodimer partner . The Journal of Biological Chemistry . 277 . 4 . 2463–7 . January 2002 . 11668176 . 10.1074/jbc.M105161200 . free .
10. 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 . September 2002 . 12198243 . 10.1210/me.2001-0194 . free .
11. Nishizawa H, Yamagata K, Shimomura I, Takahashi M, Kuriyama H, Kishida K, Hotta K, Nagaretani H, Maeda N, Matsuda M, Kihara S, Nakamura T, Nishigori H, Tomura H, Moore DD, Takeda J, Funahashi T, Matsuzawa Y . 6 . Small heterodimer partner, an orphan nuclear receptor, augments peroxisome proliferator-activated receptor gamma transactivation . The Journal of Biological Chemistry . 277 . 2 . 1586–92 . January 2002 . 11696534 . 10.1074/jbc.M104301200 . free .
12. Seol W, Choi HS, Moore DD . An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors . Science . 272 . 5266 . 1336–9 . May 1996 . 8650544 . 10.1126/science.272.5266.1336 . 1996Sci...272.1336S . 32853062 .
13. Seol W, Hanstein B, Brown M, Moore DD . Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner) . Molecular Endocrinology . 12 . 10 . 1551–7 . October 1998 . 9773978 . 10.1210/me.12.10.1551 . free .
14. Zhi X, Zhou XE, He Y, Zechner C, Suino-Powell KM, Kliewer SA, Melcher K, Mangelsdorf DJ, Xu HE . 6 . Structural insights into gene repression by the orphan nuclear receptor SHP . Proceedings of the National Academy of Sciences of the United States of America . 111 . 2 . 839–44 . January 2014 . 24379397 . 10.1073/pnas.1322827111 . 3896210 . 2014PNAS..111..839Z . free .