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Structural highlights
Function
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]
Publication Abstract from PubMed
The proteasome holoenzyme is activated by its regulatory particle (RP) consisting of two subcomplexes, the lid and the base. A key event in base assembly is the formation of a heterohexameric ring of AAA-ATPases, which is guided by at least four RP assembly chaperones in mammals: PAAF1, p28/gankyrin, p27/PSMD9, and S5b. Using cryogenic electron microscopy, we analyzed the non-AAA structure of the p28-bound human RP at 4.5 A resolution and determined seven distinct conformations of the Rpn1-p28-AAA subcomplex within the p28-bound RP at subnanometer resolutions. Remarkably, the p28-bound AAA ring does not form a channel in the free RP and spontaneously samples multiple "open" and "closed" topologies at the Rpt2-Rpt6 and Rpt3-Rpt4 interfaces. Our analysis suggests that p28 assists the proteolytic core particle to select a specific conformation of the ATPase ring for RP engagement and is released in a shoehorn-like fashion in the last step of the chaperone-mediated proteasome assembly.
Conformational Landscape of the p28-Bound Human Proteasome Regulatory Particle.,Lu Y, Wu J, Dong Y, Chen S, Sun S, Ma YB, Ouyang Q, Finley D, Kirschner MW, Mao Y Mol Cell. 2017 Jul 20;67(2):322-333.e6. doi: 10.1016/j.molcel.2017.06.007. Epub, 2017 Jul 6. PMID:28689658[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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:https://dx.doi.org/10.1038/71600
- ↑ 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
- ↑ 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:https://dx.doi.org/10.1074/jbc.M107313200
- ↑ 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:https://dx.doi.org/10.1016/j.ccr.2005.06.006
- ↑ 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:https://dx.doi.org/10.1038/cr.2007.99
- ↑ 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:https://dx.doi.org/10.1016/j.cell.2009.05.008
- ↑ 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:https://dx.doi.org/10.1159/000227831
- ↑ 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:https://dx.doi.org/10.1172/JCI42542
- ↑ 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:https://dx.doi.org/10.1038/71600
- ↑ 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
- ↑ 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:https://dx.doi.org/10.1074/jbc.M107313200
- ↑ 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:https://dx.doi.org/10.1016/j.ccr.2005.06.006
- ↑ 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:https://dx.doi.org/10.1038/cr.2007.99
- ↑ 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:https://dx.doi.org/10.1016/j.cell.2009.05.008
- ↑ 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:https://dx.doi.org/10.1159/000227831
- ↑ 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:https://dx.doi.org/10.1172/JCI42542
- ↑ 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:https://dx.doi.org/10.1016/j.molcel.2017.06.007
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