| Structural highlights
6msb is a 48 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: | PSMD1 (HUMAN), PSMD8 (HUMAN), SEM1, C7orf76, DSS1, SHFDG1, SHFM1 (HUMAN), PSMD2, TRAP2 (HUMAN), PSMC2, MSS1 (HUMAN), PSMC1 (HUMAN), PSMC5, SUG1 (HUMAN), PSMC4, MIP224, TBP7 (HUMAN), PSMC6 (HUMAN), PSMC3, TBP1 (HUMAN), PSMD3 (HUMAN), PSMA6, PROS27 (HUMAN), PSMA2, HC3, PSC3 (HUMAN), PSMA4, HC9, PSC9 (HUMAN), PSMA7, HSPC (HUMAN), PSMA5 (HUMAN), PSMA1, HC2, NU, PROS30, PSC2 (HUMAN), PSMA3, HC8, PSC8 (HUMAN), PSMB6, LMPY, Y (HUMAN), PSMB7, Z (HUMAN), PSMB3 (HUMAN), PSMD12 (HUMAN), PSMB2 (HUMAN), PSMB5, LMPX, MB1, X (HUMAN), PSMB1, PSC5 (HUMAN), PSMB4, PROS26 (HUMAN), PSMD11 (HUMAN), PSMD6, KIAA0107, PFAAP4 (HUMAN), PSMD7, MOV34L (HUMAN), PSMD13 (HUMAN), PSMD4, MCB1 (HUMAN), PSMD14, POH1 (HUMAN) |
| Activity: | Proteasome endopeptidase complex, with EC number 3.4.25.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[SEM1_HUMAN] Split hand-split foot malformation.
Function
[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.[1] [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. [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. [PSD13_HUMAN] Acts as a regulatory subunit of the 26S proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. [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.[2] [3] [PSMD3_HUMAN] Acts as a regulatory subunit of the 26 proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. [PSMD1_HUMAN] Acts as a regulatory subunit of the 26 proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. [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. [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. [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.[4] [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. [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). [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. [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. [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. [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. [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. [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). [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.[5] [6] [7] [8] [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. [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.[9] [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.[10] [11] [12] [13] [14] [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. [PSMD7_HUMAN] Acts as a regulatory subunit of the 26S 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. [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.[15] [16] [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. [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. [PSMD4_HUMAN] Binds and presumably selects ubiquitin-conjugates for destruction. Displays selectivity for longer polyubiquitin chains. Modulates intestinal fluid secretion. [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.[17] [UBB_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[18] [19] [PSMD6_HUMAN] Acts as a regulatory subunit of the 26S proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins.
Publication Abstract from PubMed
The proteasome is an ATP-dependent, 2.5-megadalton machine responsible for selective protein degradation in eukaryotic cells. Here we present cryo-EM structures of the substrate-engaged human proteasome in seven conformational states at 2.8-3.6 A resolution, captured during breakdown of a polyubiquitylated protein. These structures visualize a continuum of dynamic substrate-proteasome interactions from ubiquitin recognition to substrate translocation, during which ATP hydrolysis sequentially navigates through all six ATPases. Three principal modes of coordinated hydrolysis are observed, featuring hydrolytic events in two oppositely positioned ATPases, in two adjacent ATPases, and in one ATPase at a time. These hydrolytic modes regulate deubiquitylation, translocation initiation and processive unfolding of substrates, respectively. ATP hydrolysis powers a hinge-like motion in each ATPase that regulates its substrate interaction. Synchronization of ATP binding, ADP release and ATP hydrolysis in three adjacent ATPases drives rigid-body rotations of substrate-bound ATPases that are propagated unidirectionally in the ATPase ring and unfold the substrate.
Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome.,Dong Y, Zhang S, Wu Z, Li X, Wang WL, Zhu Y, Stoilova-McPhie S, Lu Y, Finley D, Mao Y Nature. 2018 Nov 12. pii: 10.1038/s41586-018-0736-4. doi:, 10.1038/s41586-018-0736-4. PMID:30479383[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell. 2006 Mar 17;21(6):737-48. PMID:16543144 doi:S1097-2765(06)00120-1
- ↑ Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans. 2009 Oct;37(Pt 5):937-53. doi: 10.1042/BST0370937. PMID:19754430 doi:10.1042/BST0370937
- ↑ Dong Y, Zhang S, Wu Z, Li X, Wang WL, Zhu Y, Stoilova-McPhie S, Lu Y, Finley D, Mao Y. Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome. Nature. 2018 Nov 12. pii: 10.1038/s41586-018-0736-4. doi:, 10.1038/s41586-018-0736-4. PMID:30479383 doi:http://dx.doi.org/10.1038/s41586-018-0736-4
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