SHP (タンパク質)
SHP（small heterodimer partner）もしくはNR0B2（nuclear receptor subfamily 0 group B member 2）は、ヒトではNR0B2遺伝子によってコードされているタンパク質である。SHPは核内受容体ファミリーに属するが、DNA結合ドメインを欠いているという点で例外的存在である。そのため厳密には転写因子でも核内受容体でもないが、核内受容体ファミリーの他のメンバーと比較的高い配列相同性を有するためこのファミリーに分類されている。
機能
SHPの主要な機能は、他の核内受容体と結合して非生産的なヘテロ二量体を形成することで、その受容体の機能を抑制することのようである。SHPは代謝と概日時計とを連結している因子としても同定されている。SHPはレチノイド受容体や甲状腺ホルモン受容体と相互作用し、リガンド依存的な転写活性化を阻害することが示されている。さらに、エストロゲン受容体とも相互作用し、機能の阻害をもたらす。SHPは、コアクチベーターとの競合、転写リプレッサーとしての機能、という2つの異なる段階でホルモン受容体を介した活性化を抑制していることが示唆されている。
構造とリガンド
SHPのリガンド結合ドメイン（LBD）は、EID1由来ペプチドとの共結晶の構造が得られている。SHPの全体構造は他の核内受容体のLBDのアポ型（リガンドを結合していない状態）の構造と類似している。EID1は核内受容体がコアクチベーターとの相互作用に利用するAF-2部位ではなく、他のLBDのヘリックス1を模倣する形でSHPに結合する。一部の合成レチノイドリガンドはSHPのLBDに結合し、LXXLLモチーフを有するコリプレッサーとのAF-2部位を介した相互作用を促進する。
相互作用
中規模・大規模スケールの酵母ツーハイブリッド法実験や核内受容体に関する文献のテキストマイニングにより、SHPが核内受容体の二量体化ネットワークに重要な役割を果たしており、他の核内受容体と比較して高度に連結されたハブとなっていることが明らかにされている。
SHPは次に挙げる因子と相互作用することが示されている。
出典
- 1 2 3 GRCh38: Ensembl release 89: ENSG00000131910 - Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000037583 - Ensembl, May 2017
- ↑ Human PubMed Reference:
- ↑ Mouse PubMed Reference:
- 1 2 “Entrez Gene: NR0B2 nuclear receptor subfamily 0, group B, member 2”. 2025年12月31日閲覧。
- ↑ Lee HK, Lee YK, Park SH, Kim YS, Park SH, Lee JW, Kwon HB, Soh J, Moore DD, Choi HS (June 1998). “Structure and expression of the orphan nuclear receptor SHP gene”. The Journal of Biological Chemistry 273 (23): 14398–402. doi:10.1074/jbc.273.23.14398. PMID 9603951.
- ↑ Båvner A, Sanyal S, Gustafsson JA, Treuter E (December 2005). “Transcriptional corepression by SHP: molecular mechanisms and physiological consequences”. Trends in Endocrinology and Metabolism 16 (10): 478–88. doi:10.1016/j.tem.2005.10.005. PMID 16275121.
- ↑ Wu N, Kim KH, Zhou Y, Lee JM, Kettner NM, Mamrosh JL, Choi S, Fu L, Moore DD (September 2016). “Small Heterodimer Partner (NR0B2) Coordinates Nutrient Signaling and the Circadian Clock in Mice”. Molecular Endocrinology 30 (9): 988–95. doi:10.1210/me.2015-1295. PMC 5004116. PMID 27427832.
- ↑ Zhi, Xiaoyong; Zhou, X. Edward; He, Yuanzheng; Zechner, Christoph; Suino-Powell, Kelly M.; Kliewer, Steven A.; Melcher, Karsten; Mangelsdorf, David J. et al. (2014-01-14). “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): 839–844. doi:10.1073/pnas.1322827111. ISSN 1091-6490. PMC 3896210. PMID 24379397.
- ↑ Amoutzias GD, Pichler EE, Mian N, De Graaf D, Imsiridou A, Robinson-Rechavi M, Bornberg-Bauer E, Robertson DL, Oliver SG (July 2007). “A protein interaction atlas for the nuclear receptors: properties and quality of a hub-based dimerisation network”. BMC Systems Biology 1: 34. doi:10.1186/1752-0509-1-34. PMC 1971058. PMID 17672894.
- ↑ Gobinet J, Auzou G, Nicolas JC, Sultan C, Jalaguier S (December 2001). “Characterization of the interaction between androgen receptor and a new transcriptional inhibitor, SHP”. Biochemistry 40 (50): 15369–77. doi:10.1021/bi011384o. PMID 11735420.
- ↑ Klinge CM, Jernigan SC, Risinger KE (March 2002). “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. doi:10.1210/endo.143.3.8676. PMID 11861507.
- 1 2 Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD (January 2000). “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. doi:10.1128/MCB.20.1.187-195.2000. PMC 85074. PMID 10594021.
- 1 2 3 Brendel C, Schoonjans K, Botrugno OA, Treuter E, Auwerx J (September 2002). “The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity”. Molecular Endocrinology 16 (9): 2065–76. doi:10.1210/me.2001-0194. PMID 12198243.
- ↑ Lee YK, Moore DD (January 2002). “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. doi:10.1074/jbc.M105161200. PMID 11668176.
- ↑ 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 (January 2002). “Small heterodimer partner, an orphan nuclear receptor, augments peroxisome proliferator-activated receptor gamma transactivation”. The Journal of Biological Chemistry 277 (2): 1586–92. doi:10.1074/jbc.M104301200. PMID 11696534.
- ↑ Seol W, Choi HS, Moore DD (May 1996). “An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors”. Science 272 (5266): 1336–9. Bibcode:1996Sci...272.1336S. doi:10.1126/science.272.5266.1336. PMID 8650544.
- ↑ Seol W, Hanstein B, Brown M, Moore DD (October 1998). “Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner)”. Molecular Endocrinology 12 (10): 1551–7. doi:10.1210/me.12.10.1551. PMID 9773978.
- ↑ Zhi X, Zhou XE, He Y, Zechner C, Suino-Powell KM, Kliewer SA, Melcher K, Mangelsdorf DJ, Xu HE (January 2014). “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. Bibcode:2014PNAS..111..839Z. doi:10.1073/pnas.1322827111. PMC 3896210. PMID 24379397.
関連文献
- Seol W, Choi HS, Moore DD (May 1996). “An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors”. Science 272 (5266): 1336–9. Bibcode:1996Sci...272.1336S. doi:10.1126/science.272.5266.1336. PMID 8650544.
- Seol W, Hanstein B, Brown M, Moore DD (October 1998). “Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner)”. Molecular Endocrinology 12 (10): 1551–7. doi:10.1210/me.12.10.1551. PMID 9773978.
- Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD (January 2000). “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. doi:10.1128/MCB.20.1.187-195.2000. PMC 85074. PMID 10594021.
- Johansson L, Båvner A, Thomsen JS, Färnegårdh M, Gustafsson JA, Treuter E (February 2000). “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. doi:10.1128/MCB.20.4.1124-1133.2000. PMC 85230. PMID 10648597.
- Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ (September 2000). “Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors”. Molecular Cell 6 (3): 507–15. doi:10.1016/S1097-2765(00)00050-2. PMID 11030331.
- 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 (January 2001). “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. doi:10.1073/pnas.021544398. PMC 14629. PMID 11136233.
- Lee YK, Moore DD (January 2002). “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. doi:10.1074/jbc.M105161200. PMID 11668176.
- 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 (January 2002). “Small heterodimer partner, an orphan nuclear receptor, augments peroxisome proliferator-activated receptor gamma transactivation”. The Journal of Biological Chemistry 277 (2): 1586–92. doi:10.1074/jbc.M104301200. PMID 11696534.
- Sanyal S, Kim JY, Kim HJ, Takeda J, Lee YK, Moore DD, Choi HS (January 2002). “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. doi:10.1074/jbc.M106140200. PMID 11705994.
- Gobinet J, Auzou G, Nicolas JC, Sultan C, Jalaguier S (December 2001). “Characterization of the interaction between androgen receptor and a new transcriptional inhibitor, SHP”. Biochemistry 40 (50): 15369–77. doi:10.1021/bi011384o. PMID 11735420.
- Klinge CM, Jernigan SC, Risinger KE (March 2002). “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. doi:10.1210/endo.143.3.8676. PMID 11861507.
- Ogata M, Awaji T, Iwasaki N, Miyazaki S, Bell GI, Iwamoto Y (March 2002). “Nuclear translocation of SHP and visualization of interaction with HNF-4alpha in living cells”. Biochemical and Biophysical Research Communications 292 (1): 8–12. doi:10.1006/bbrc.2002.6593. PMID 11890664.
- Cao H, Hegele RA (2002). “Identification of polymorphisms in the human SHP1 gene”. Journal of Human Genetics 47 (8): 445–7. doi:10.1007/s100380200062. PMID 12181644.
- Brendel C, Schoonjans K, Botrugno OA, Treuter E, Auwerx J (September 2002). “The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity”. Molecular Endocrinology 16 (9): 2065–76. doi:10.1210/me.2001-0194. PMID 12198243.
- Borgius LJ, Steffensen KR, Gustafsson JA, Treuter E (December 2002). “Glucocorticoid signaling is perturbed by the atypical orphan receptor and corepressor SHP”. The Journal of Biological Chemistry 277 (51): 49761–6. doi:10.1074/jbc.M205641200. PMID 12324453.
- Hung CC, Farooqi IS, Ong K, Luan J, Keogh JM, Pembrey M, Yeo GS, Dunger D, Wareham NJ, O' Rahilly S (May 2003). “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. doi:10.2337/diabetes.52.5.1288. PMID 12716767.
- Lai K, Harnish DC, Evans MJ (September 2003). “Estrogen receptor alpha regulates expression of the orphan receptor small heterodimer partner”. The Journal of Biological Chemistry 278 (38): 36418–29. doi:10.1074/jbc.M303913200. PMID 12842887.
- Kovacic A, Speed CJ, Simpson ER, Clyne CD (January 2004). “Inhibition of aromatase transcription via promoter II by short heterodimer partner in human preadipocytes”. Molecular Endocrinology 18 (1): 252–9. doi:10.1210/me.2003-0211. PMID 14593077.