5vhi

Structural highlights

Disease

[SEM1_HUMAN] Split hand-split foot malformation.

Function

[PRS6A_HUMAN] The 26S protease is involved in the ATP-dependent degradation of ubiquitinated proteins. The regulatory (or ATPase) complex confers ATP dependency and substrate specificity to the 26S complex (By similarity). In case of HIV-1 infection, suppresses Tat-mediated transactivation. [PSMD6_HUMAN] Acts as a regulatory subunit of the 26S proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. [PRS8_HUMAN] The 26S protease is involved in the ATP-dependent degradation of ubiquitinated proteins. The regulatory (or ATPase) complex confers ATP dependency and substrate specificity to the 26S complex. [PSMD1_HUMAN] Acts as a regulatory subunit of the 26 proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. [PSD12_HUMAN] Acts as a regulatory subunit of the 26S proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. [PRS4_HUMAN] The 26S protease is involved in the ATP-dependent degradation of ubiquitinated proteins. The regulatory (or ATPase) complex confers ATP dependency and substrate specificity to the 26S complex. [PSD10_HUMAN] Acts as a chaperone during the assembly of the 26S proteasome, specifically of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD10:PSMC4:PSMC5:PAAF1 module which probably assembles with a PSMD5:PSMC2:PSMC1:PSMD2 module. Independently of the proteasome, regulates EGF-induced AKT activation through inhibition of the RHOA/ROCK/PTEN pahway, leading to prolonged AKT activation. Plays an important role in RAS-induced tumorigenesis.^{[1] [2] [3] [4] [5] [6] [7] [8]} Acts as an proto-oncoprotein by being involved in negative regulation of tumor suppressors RB1 and p53/TP53. Overexpression is leading to phosphorylation of RB1 and proteasomal degradation of RB1. Regulates CDK4-mediated phosphorylation of RB1 by competing with CDKN2A for binding with CDK4. Facilitates binding of MDM2 to p53/TP53 and the mono- and polyubiquitination of p53/TP53 by MDM2 suggesting a function in targeting the TP53:MDM2 complex to the 26S proteasome. Involved in p53-independent apoptosis. Involved in regulation of NF-kappa-B by retaining it in the cytoplasm. Binds to the NF-kappa-B component RELA and accelerates its XPO1/CRM1-mediated nuclear export.^{[9] [10] [11] [12] [13] [14] [15] [16]} [PSMD7_HUMAN] Acts as a regulatory subunit of the 26S proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. [PSDE_HUMAN] Metalloprotease component of the 26S proteasome that specifically cleaves 'Lys-63'-linked polyubiquitin chains. The 26S proteasome is involved in the ATP-dependent degradation of ubiquitinated proteins. Plays a role in response to double-strand breaks (DSBs): acts as a regulator of non-homologous end joining (NHEJ) by cleaving 'Lys-63'-linked polyubiquitin, thereby promoting retention of JMJD2A/KDM4A on chromatin and restricting TP53BP1 accumulation. Also involved in homologous recombination repair by promoting RAD51 loading.^{[17] [18]} [PSMD4_HUMAN] Binds and presumably selects ubiquitin-conjugates for destruction. Displays selectivity for longer polyubiquitin chains. Modulates intestinal fluid secretion. [PSMD3_HUMAN] Acts as a regulatory subunit of the 26 proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. [PRS6B_HUMAN] The 26S protease is involved in the ATP-dependent degradation of ubiquitinated proteins. The regulatory (or ATPase) complex confers ATP dependency and substrate specificity to the 26S complex.^[19] [PRS7_HUMAN] The 26S protease is involved in the ATP-dependent degradation of ubiquitinated proteins. The regulatory (or ATPase) complex confers ATP dependency and substrate specificity to the 26S complex. In case of HIV-1 infection, positive modulator of Tat-mediated transactivation.^[20] [SEM1_HUMAN] Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair (PubMed:15117943). Component of the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). The TREX-2 complex functions in docking export-competent ribonucleoprotein particles (mRNPs) to the nuclear entrance of the nuclear pore complex (nuclear basket). TREX-2 participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery. Binds and stabilizes BRCA2 and is thus involved in the control of R-loop-associated DNA damage and thus transcription-associated genomic instability. R-loop accumulation increases in SEM1-depleted cells.^{[21] [22] [23] [24]} [PSMD2_HUMAN] Acts as a regulatory subunit of the 26 proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. Binds to the intracellular domain of tumor necrosis factor type 1 receptor. The binding domain of TRAP1 and TRAP2 resides outside the death domain of TNFR1. [PSD11_HUMAN] Component of the lid subcomplex of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. In the complex, PSMD11 is required for proteasome assembly. Plays a key role in increased proteasome activity in embryonic stem cells (ESCs): its high expression in ESCs promotes enhanced assembly of the 26S proteasome, followed by higher proteasome activity.^[25] [PSD13_HUMAN] Acts as a regulatory subunit of the 26S proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. [PSMD8_HUMAN] Acts as a regulatory subunit of the 26S proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. Necessary for activation of the CDC28 kinase. [PRS10_HUMAN] The 26S protease is involved in the ATP-dependent degradation of ubiquitinated proteins. The regulatory (or ATPase) complex confers ATP dependency and substrate specificity to the 26S complex.

See Also

• Proteasome 3D structures

References

1. ↑ Higashitsuji H, Itoh K, Nagao T, Dawson S, Nonoguchi K, Kido T, Mayer RJ, Arii S, Fujita J. Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med. 2000 Jan;6(1):96-9. PMID:10613832 doi:http://dx.doi.org/10.1038/71600
2. ↑ Li J, Tsai MD. Novel insights into the INK4-CDK4/6-Rb pathway: counter action of gankyrin against INK4 proteins regulates the CDK4-mediated phosphorylation of Rb. Biochemistry. 2002 Mar 26;41(12):3977-83. PMID:11900540
3. ↑ Dawson S, Apcher S, Mee M, Higashitsuji H, Baker R, Uhle S, Dubiel W, Fujita J, Mayer RJ. Gankyrin is an ankyrin-repeat oncoprotein that interacts with CDK4 kinase and the S6 ATPase of the 26 S proteasome. J Biol Chem. 2002 Mar 29;277(13):10893-902. Epub 2002 Jan 4. PMID:11779854 doi:http://dx.doi.org/10.1074/jbc.M107313200
4. ↑ Higashitsuji H, Higashitsuji H, Itoh K, Sakurai T, Nagao T, Sumitomo Y, Masuda T, Dawson S, Shimada Y, Mayer RJ, Fujita J. The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell. 2005 Jul;8(1):75-87. PMID:16023600 doi:http://dx.doi.org/10.1016/j.ccr.2005.06.006
5. ↑ Chen Y, Li HH, Fu J, Wang XF, Ren YB, Dong LW, Tang SH, Liu SQ, Wu MC, Wang HY. Oncoprotein p28 GANK binds to RelA and retains NF-kappaB in the cytoplasm through nuclear export. Cell Res. 2007 Dec;17(12):1020-9. PMID:18040287 doi:http://dx.doi.org/10.1038/cr.2007.99
6. ↑ Kaneko T, Hamazaki J, Iemura S, Sasaki K, Furuyama K, Natsume T, Tanaka K, Murata S. Assembly pathway of the Mammalian proteasome base subcomplex is mediated by multiple specific chaperones. Cell. 2009 May 29;137(5):914-25. doi: 10.1016/j.cell.2009.05.008. PMID:19490896 doi:http://dx.doi.org/10.1016/j.cell.2009.05.008
7. ↑ Wang J, Wang XF, Zhang LG, Xie SY, Li ZL, Li YJ, Li HH, Jiao F. Involvement of the mitochondrial pathway in p53-independent apoptosis induced by p28GANK knockdown in Hep3B cells. Cytogenet Genome Res. 2009;125(2):87-97. doi: 10.1159/000227831. Epub 2009 Aug, 31. PMID:19729910 doi:http://dx.doi.org/10.1159/000227831
8. ↑ Man JH, Liang B, Gu YX, Zhou T, Li AL, Li T, Jin BF, Bai B, Zhang HY, Zhang WN, Li WH, Gong WL, Li HY, Zhang XM. Gankyrin plays an essential role in Ras-induced tumorigenesis through regulation of the RhoA/ROCK pathway in mammalian cells. J Clin Invest. 2010 Aug;120(8):2829-41. doi: 10.1172/JCI42542. Epub 2010 Jul 12. PMID:20628200 doi:http://dx.doi.org/10.1172/JCI42542
9. ↑ Higashitsuji H, Itoh K, Nagao T, Dawson S, Nonoguchi K, Kido T, Mayer RJ, Arii S, Fujita J. Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med. 2000 Jan;6(1):96-9. PMID:10613832 doi:http://dx.doi.org/10.1038/71600
10. ↑ Li J, Tsai MD. Novel insights into the INK4-CDK4/6-Rb pathway: counter action of gankyrin against INK4 proteins regulates the CDK4-mediated phosphorylation of Rb. Biochemistry. 2002 Mar 26;41(12):3977-83. PMID:11900540
11. ↑ Dawson S, Apcher S, Mee M, Higashitsuji H, Baker R, Uhle S, Dubiel W, Fujita J, Mayer RJ. Gankyrin is an ankyrin-repeat oncoprotein that interacts with CDK4 kinase and the S6 ATPase of the 26 S proteasome. J Biol Chem. 2002 Mar 29;277(13):10893-902. Epub 2002 Jan 4. PMID:11779854 doi:http://dx.doi.org/10.1074/jbc.M107313200
12. ↑ Higashitsuji H, Higashitsuji H, Itoh K, Sakurai T, Nagao T, Sumitomo Y, Masuda T, Dawson S, Shimada Y, Mayer RJ, Fujita J. The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell. 2005 Jul;8(1):75-87. PMID:16023600 doi:http://dx.doi.org/10.1016/j.ccr.2005.06.006
13. ↑ Chen Y, Li HH, Fu J, Wang XF, Ren YB, Dong LW, Tang SH, Liu SQ, Wu MC, Wang HY. Oncoprotein p28 GANK binds to RelA and retains NF-kappaB in the cytoplasm through nuclear export. Cell Res. 2007 Dec;17(12):1020-9. PMID:18040287 doi:http://dx.doi.org/10.1038/cr.2007.99
14. ↑ Kaneko T, Hamazaki J, Iemura S, Sasaki K, Furuyama K, Natsume T, Tanaka K, Murata S. Assembly pathway of the Mammalian proteasome base subcomplex is mediated by multiple specific chaperones. Cell. 2009 May 29;137(5):914-25. doi: 10.1016/j.cell.2009.05.008. PMID:19490896 doi:http://dx.doi.org/10.1016/j.cell.2009.05.008
15. ↑ Wang J, Wang XF, Zhang LG, Xie SY, Li ZL, Li YJ, Li HH, Jiao F. Involvement of the mitochondrial pathway in p53-independent apoptosis induced by p28GANK knockdown in Hep3B cells. Cytogenet Genome Res. 2009;125(2):87-97. doi: 10.1159/000227831. Epub 2009 Aug, 31. PMID:19729910 doi:http://dx.doi.org/10.1159/000227831
16. ↑ Man JH, Liang B, Gu YX, Zhou T, Li AL, Li T, Jin BF, Bai B, Zhang HY, Zhang WN, Li WH, Gong WL, Li HY, Zhang XM. Gankyrin plays an essential role in Ras-induced tumorigenesis through regulation of the RhoA/ROCK pathway in mammalian cells. J Clin Invest. 2010 Aug;120(8):2829-41. doi: 10.1172/JCI42542. Epub 2010 Jul 12. PMID:20628200 doi:http://dx.doi.org/10.1172/JCI42542
17. ↑ Butler LR, Densham RM, Jia J, Garvin AJ, Stone HR, Shah V, Weekes D, Festy F, Beesley J, Morris JR. The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response. EMBO J. 2012 Oct 3;31(19):3918-34. doi: 10.1038/emboj.2012.232. Epub 2012 Aug 21. PMID:22909820 doi:http://dx.doi.org/10.1038/emboj.2012.232
18. ↑ Spataro V, Toda T, Craig R, Seeger M, Dubiel W, Harris AL, Norbury C. Resistance to diverse drugs and ultraviolet light conferred by overexpression of a novel human 26 S proteasome subunit. J Biol Chem. 1997 Nov 28;272(48):30470-5. PMID:9374539
19. ↑ Dubiel W, Ferrell K, Rechsteiner M. Tat-binding protein 7 is a subunit of the 26S protease. Biol Chem Hoppe Seyler. 1994 Apr;375(4):237-40. PMID:8060531
20. ↑ Chen Y, Sharp ZD, Lee WH. HEC binds to the seventh regulatory subunit of the 26 S proteasome and modulates the proteolysis of mitotic cyclins. J Biol Chem. 1997 Sep 19;272(38):24081-7. PMID:9295362
21. ↑ Kanayama HO, Tamura T, Ugai S, Kagawa S, Tanahashi N, Yoshimura T, Tanaka K, Ichihara A. Demonstration that a human 26S proteolytic complex consists of a proteasome and multiple associated protein components and hydrolyzes ATP and ubiquitin-ligated proteins by closely linked mechanisms. Eur J Biochem. 1992 Jun 1;206(2):567-78. PMID:1317798
22. ↑ Sone T, Saeki Y, Toh-e A, Yokosawa H. Sem1p is a novel subunit of the 26 S proteasome from Saccharomyces cerevisiae. J Biol Chem. 2004 Jul 2;279(27):28807-16. Epub 2004 Apr 26. PMID:15117943 doi:http://dx.doi.org/10.1074/jbc.M403165200
23. ↑ Jani D, Lutz S, Hurt E, Laskey RA, Stewart M, Wickramasinghe VO. Functional and structural characterization of the mammalian TREX-2 complex that links transcription with nuclear messenger RNA export. Nucleic Acids Res. 2012 May 1;40(10):4562-73. Epub 2012 Feb 4. PMID:22307388 doi:10.1093/nar/gks059
24. ↑ Bhatia V, Barroso SI, Garcia-Rubio ML, Tumini E, Herrera-Moyano E, Aguilera A. BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature. 2014 Jul 17;511(7509):362-5. doi: 10.1038/nature13374. Epub 2014 Jun 1. PMID:24896180 doi:http://dx.doi.org/10.1038/nature13374
25. ↑ Vilchez D, Boyer L, Morantte I, Lutz M, Merkwirth C, Joyce D, Spencer B, Page L, Masliah E, Berggren WT, Gage FH, Dillin A. Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature. 2012 Sep 13;489(7415):304-8. doi: 10.1038/nature11468. PMID:22972301 doi:http://dx.doi.org/10.1038/nature11468
26. ↑ Lu Y, Wu J, Dong Y, Chen S, Sun S, Ma YB, Ouyang Q, Finley D, Kirschner MW, Mao Y. Conformational Landscape of the p28-Bound Human Proteasome Regulatory Particle. Mol Cell. 2017 Jul 20;67(2):322-333.e6. doi: 10.1016/j.molcel.2017.06.007. Epub, 2017 Jul 6. PMID:28689658 doi:http://dx.doi.org/10.1016/j.molcel.2017.06.007