| Structural highlights
6kwy is a 29 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Gene: | PSMA2, HC3, PSC3 (HUMAN), PSMB2 (HUMAN), PSMB5, LMPX, MB1, X (HUMAN), PSMB1, PSC5 (HUMAN), PSMB4, PROS26 (HUMAN), PSMB6, LMPY, Y (HUMAN), PSME4, KIAA0077 (HUMAN), PSMA4, HC9, PSC9 (HUMAN), PSMA7, HSPC (HUMAN), PSMA5 (HUMAN), PSMA1, HC2, NU, PROS30, PSC2 (HUMAN), PSMA3, HC8, PSC8 (HUMAN), PSMA6, PROS27 (HUMAN), PSMB7, Z (HUMAN), PSMB3 (HUMAN) |
| Activity: | Proteasome endopeptidase complex, with EC number 3.4.25.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[PSA3_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Binds to the C-terminus of CDKN1A and thereby mediates its degradation. Negatively regulates the membrane trafficking of the cell-surface thromboxane A2 receptor (TBXA2R) isoform 2.[1] [2] [PSB5_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This unit is responsible of the chymotrypsin-like activity of the proteasome and is one of the principal target of the proteasome inhibitor bortezomib. May catalyze basal processing of intracellular antigens. Plays a role in the protection against oxidative damage through the Nrf2-ARE pathway (By similarity). [PSA7_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Plays an important role in the regulation of cell proliferation or cell cycle control, transcriptional regulation, immune and stress response, cell differentiation, and apoptosis. Interacts with some important proteins involved in transcription factor regulation, cell cycle transition, viral replication and even tumor initiation and progression. Inhibits the transactivation function of HIF-1A under both normoxic and hypoxia-mimicking conditions. The interaction with EMAP2 increases the proteasome-mediated HIF-1A degradation under the hypoxic conditions. Plays a role in hepatitis C virus internal ribosome entry site-mediated translation. Mediates nuclear translocation of the androgen receptor (AR) and thereby enhances androgen-mediated transactivation. Promotes MAVS degradation and thereby negatively regulates MAVS-mediated innate immune response.[3] [4] [5] [6] [7] [PSA6_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. [PSB3_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. [PSB1_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. [PSA4_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. [PSME4_HUMAN] Associated component of the proteasome that specifically recognizes acetylated histones and promotes ATP- and ubiquitin-independent degradation of core histones during spermatogenesis and DNA damage response. Recognizes and binds acetylated histones via its bromodomain-like (BRDL) region and activates the proteasome by opening the gated channel for substrate entry. Binds to the core proteasome via its C-terminus, which occupies the same binding sites as the proteasomal ATPases, opening the closed structure of the proteasome via an active gating mechanism. Component of the spermatoproteasome, a form of the proteasome specifically found in testis: binds to acetylated histones and promotes degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. Also involved in DNA damage response in somatic cells, by promoting degradation of histones following DNA double-strand breaks.[8] [9] [10] [11] [PSB6_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This unit is responsible of the peptidyl glutamyl-like activity. May catalyze basal processing of intracellular antigens. [PSB7_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This unit is responsible of the trypsin-like activity. [PSA2_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. PSMA2 may have a potential regulatory effect on another component(s) of the proteasome complex through tyrosine phosphorylation. [PSA5_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. [PSB4_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Mediates the lipopolysaccharide-induced signal macrophage proteasome (By similarity). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.[12] [PSB2_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit has a trypsin-like activity. [PSA1_HUMAN] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Mediates the lipopolysaccharide-induced signal transduction in the macrophage proteasome (By similarity). Might be involved in the anti-inflammatory response of macrophages during the interaction with C.albicans heat-inactivated cells (By similarity).
Publication Abstract from PubMed
Proteasomes are highly abundant and conserved protease complexes that eliminate unwanted proteins in the cells. As a single-chain ATP-independent nuclear proteasome activator, proteasome activator 200 (PA200) associates with 20S core particle to form proteasome complex that catalyzes polyubiquitin-independent degradation of acetylated histones, thus playing a pivotal role in DNA repair and spermatogenesis. Here, we present cryo-electron microscopy (cryo-EM) structures of the human PA200-20S complex and PA200 at 2.72 A and 3.75 A, respectively. PA200 exhibits a dome-like architecture that caps 20S and uses its C-terminal YYA (Tyr-Tyr-Ala) to induce the alpha-ring rearrangements and partial opening of the 20S gate. Our structural data also indicate that PA200 has two openings formed by numerous positively charged residues that respectively bind (5,6)-bisdiphosphoinositol tetrakisphosphate (5,6[PP]2-InsP4) and inositol hexakisphosphate (InsP6) and are likely to be the gates that lead unfolded proteins through PA200 and into the 20S. Besides, our structural analysis of PA200 found that the bromodomain (BRD)-like (BRDL) domain of PA200 shows considerable sequence variation in comparison to other human BRDs, as it contains only 82 residues because of a short ZA loop, and cannot be classified into any of the eight typical human BRD families. Taken together, the results obtained from this study provide important insights into human PA200-induced 20S gate opening for substrate degradation and the opportunities to explore the mechanism for its recognition of H4 histone in acetylation-mediated proteasomal degradation.
Cryo-EM structures of the human PA200 and PA200-20S complex reveal regulation of proteasome gate opening and two PA200 apertures.,Guan H, Wang Y, Yu T, Huang Y, Li M, Saeed AFUH, Perculija V, Li D, Xiao J, Wang D, Zhu P, Ouyang S PLoS Biol. 2020 Mar 5;18(3):e3000654. doi: 10.1371/journal.pbio.3000654., eCollection 2020 Mar. PMID:32134919[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Touitou R, Richardson J, Bose S, Nakanishi M, Rivett J, Allday MJ. A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 alpha-subunit of the 20S proteasome. EMBO J. 2001 May 15;20(10):2367-75. PMID:11350925 doi:http://dx.doi.org/10.1093/emboj/20.10.2367
- ↑ Sasaki M, Sukegawa J, Miyosawa K, Yanagisawa T, Ohkubo S, Nakahata N. Low expression of cell-surface thromboxane A2 receptor beta-isoform through the negative regulation of its membrane traffic by proteasomes. Prostaglandins Other Lipid Mediat. 2007 Jun;83(4):237-49. Epub 2006 Dec 27. PMID:17499743 doi:http://dx.doi.org/10.1016/j.prostaglandins.2006.12.001
- ↑ Cho S, Choi YJ, Kim JM, Jeong ST, Kim JH, Kim SH, Ryu SE. Binding and regulation of HIF-1alpha by a subunit of the proteasome complex, PSMA7. FEBS Lett. 2001 Jun 1;498(1):62-6. PMID:11389899
- ↑ Kruger M, Beger C, Welch PJ, Barber JR, Manns MP, Wong-Staal F. Involvement of proteasome alpha-subunit PSMA7 in hepatitis C virus internal ribosome entry site-mediated translation. Mol Cell Biol. 2001 Dec;21(24):8357-64. PMID:11713272 doi:http://dx.doi.org/10.1128/MCB.21.24.8357-8364.2001
- ↑ Lin HK, Altuwaijri S, Lin WJ, Kan PY, Collins LL, Chang C. Proteasome activity is required for androgen receptor transcriptional activity via regulation of androgen receptor nuclear translocation and interaction with coregulators in prostate cancer cells. J Biol Chem. 2002 Sep 27;277(39):36570-6. Epub 2002 Jul 15. PMID:12119296 doi:http://dx.doi.org/10.1074/jbc.M204751200
- ↑ Du H, Huang X, Wang S, Wu Y, Xu W, Li M. PSMA7, a potential biomarker of diseases. Protein Pept Lett. 2009;16(5):486-9. PMID:19442227
- ↑ Jia Y, Song T, Wei C, Ni C, Zheng Z, Xu Q, Ma H, Li L, Zhang Y, He X, Xu Y, Shi W, Zhong H. Negative regulation of MAVS-mediated innate immune response by PSMA7. J Immunol. 2009 Oct 1;183(7):4241-8. doi: 10.4049/jimmunol.0901646. Epub 2009 Sep, 4. PMID:19734229 doi:http://dx.doi.org/10.4049/jimmunol.0901646
- ↑ Ustrell V, Hoffman L, Pratt G, Rechsteiner M. PA200, a nuclear proteasome activator involved in DNA repair. EMBO J. 2002 Jul 1;21(13):3516-25. doi: 10.1093/emboj/cdf333. PMID:12093752 doi:http://dx.doi.org/10.1093/emboj/cdf333
- ↑ Blickwedehl J, Agarwal M, Seong C, Pandita RK, Melendy T, Sung P, Pandita TK, Bangia N. Role for proteasome activator PA200 and postglutamyl proteasome activity in genomic stability. Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16165-70. doi:, 10.1073/pnas.0803145105. Epub 2008 Oct 9. PMID:18845680 doi:http://dx.doi.org/10.1073/pnas.0803145105
- ↑ Blickwedehl J, Olejniczak S, Cummings R, Sarvaiya N, Mantilla A, Chanan-Khan A, Pandita TK, Schmidt M, Thompson CB, Bangia N. The proteasome activator PA200 regulates tumor cell responsiveness to glutamine and resistance to ionizing radiation. Mol Cancer Res. 2012 Jul;10(7):937-44. doi: 10.1158/1541-7786.MCR-11-0493-T. Epub, 2012 May 1. PMID:22550082 doi:http://dx.doi.org/10.1158/1541-7786.MCR-11-0493-T
- ↑ Qian MX, Pang Y, Liu CH, Haratake K, Du BY, Ji DY, Wang GF, Zhu QQ, Song W, Yu Y, Zhang XX, Huang HT, Miao S, Chen LB, Zhang ZH, Liang YN, Liu S, Cha H, Yang D, Zhai Y, Komatsu T, Tsuruta F, Li H, Cao C, Li W, Li GH, Cheng Y, Chiba T, Wang L, Goldberg AL, Shen Y, Qiu XB. Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis. Cell. 2013 May 23;153(5):1012-24. doi: 10.1016/j.cell.2013.04.032. PMID:23706739 doi:http://dx.doi.org/10.1016/j.cell.2013.04.032
- ↑ Lin Y, Martin J, Gruendler C, Farley J, Meng X, Li BY, Lechleider R, Huff C, Kim RH, Grasser WA, Paralkar V, Wang T. A novel link between the proteasome pathway and the signal transduction pathway of the bone morphogenetic proteins (BMPs). BMC Cell Biol. 2002 Jun 21;3:15. PMID:12097147
- ↑ Guan H, Wang Y, Yu T, Huang Y, Li M, Saeed AFUH, Perculija V, Li D, Xiao J, Wang D, Zhu P, Ouyang S. Cryo-EM structures of the human PA200 and PA200-20S complex reveal regulation of proteasome gate opening and two PA200 apertures. PLoS Biol. 2020 Mar 5;18(3):e3000654. doi: 10.1371/journal.pbio.3000654., eCollection 2020 Mar. PMID:32134919 doi:http://dx.doi.org/10.1371/journal.pbio.3000654
|
