5m32
From Proteopedia
Human 26S proteasome in complex with Oprozomib
Structural highlights
Disease[SEM1_HUMAN] Split hand-split foot malformation. Function[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.[1] [2] [3] [4] [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. [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. [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. [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.[5] [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.[6] [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. [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. [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. [PSMD4_HUMAN] Binds and presumably selects ubiquitin-conjugates for destruction. Displays selectivity for longer polyubiquitin chains. Modulates intestinal fluid secretion. [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). [PSMD6_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. [PSMD7_HUMAN] Acts as a regulatory subunit of the 26S proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. [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. [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. [PSMD3_HUMAN] Acts as a regulatory subunit of the 26 proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. [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. [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.[7] [8] [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). [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. [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.[9] [PSMD1_HUMAN] Acts as a regulatory subunit of the 26 proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins. [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.[10] [11] [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.[12] [13] [14] [15] [16] [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. [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. [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. [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.[17] Publication Abstract from PubMedThe proteasome holoenzyme is the major non-lysosomal protease; its proteolytic activity is essential for cellular homeostasis. Thus, it is an attractive target for the development of chemotherapeutics. While the structural basis of core particle (CP) inhibitors is largely understood, their structural impact on the proteasome holoenzyme remains entirely elusive. Here, we determined the structure of the 26S proteasome with and without the inhibitor Oprozomib. Drug binding modifies the energy landscape of conformational motion in the proteasome regulatory particle (RP). Structurally, the energy barrier created by Oprozomib triggers a long-range allosteric regulation, resulting in the stabilization of a non-productive state. Thereby, the chemical drug-binding signal is converted, propagated and amplified into structural changes over a distance of more than 150 A from the proteolytic site to the ubiquitin receptor Rpn10. The direct visualization of changes in conformational dynamics upon drug binding allows new ways to screen and develop future allosteric proteasome inhibitors. Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs.,Haselbach D, Schrader J, Lambrecht F, Henneberg F, Chari A, Stark H Nat Commun. 2017 May 25;8:15578. doi: 10.1038/ncomms15578. PMID:28541292[18] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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