+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-40789 | ||||||||||||
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Title | BAP1/ASXL1 bound to the H2AK119Ub Nucleosome | ||||||||||||
Map data | Sharpened map DNA clamp BAP1/ASXL1-H2AK119Ub nucleosome complex | ||||||||||||
Sample |
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Keywords | DNA complex protein / hydrolase / structural protein / NUCLEAR PROTEIN-DNA-RNA complex | ||||||||||||
Function / homology | Function and homology information thrombocyte differentiation / nucleate erythrocyte differentiation / negative regulation of peroxisome proliferator activated receptor signaling pathway / PR-DUB complex / leukocyte proliferation / platelet morphogenesis / histone H2A deubiquitinase activity / positive regulation of retinoic acid receptor signaling pathway / macrophage homeostasis / lung saccule development ...thrombocyte differentiation / nucleate erythrocyte differentiation / negative regulation of peroxisome proliferator activated receptor signaling pathway / PR-DUB complex / leukocyte proliferation / platelet morphogenesis / histone H2A deubiquitinase activity / positive regulation of retinoic acid receptor signaling pathway / macrophage homeostasis / lung saccule development / podocyte development / neutrophil differentiation / regulation of kidney size / myeloid cell apoptotic process / hematopoietic stem cell homeostasis / monoubiquitinated protein deubiquitination / common myeloid progenitor cell proliferation / protein K48-linked deubiquitination / tissue homeostasis / nuclear retinoic acid receptor binding / peroxisome proliferator activated receptor binding / bone marrow development / positive regulation of protein targeting to mitochondrion / negative regulation of fat cell differentiation / protein deubiquitination / erythrocyte maturation / regulation of cytokine production involved in inflammatory response / hemopoiesis / homeostasis of number of cells / : / heart morphogenesis / response to retinoic acid / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / Prevention of phagosomal-lysosomal fusion / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Membrane binding and targetting of GAG proteins / Endosomal Sorting Complex Required For Transport (ESCRT) / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Negative regulation of FLT3 / Constitutive Signaling by NOTCH1 HD Domain Mutants / Regulation of FZD by ubiquitination / TICAM1,TRAF6-dependent induction of TAK1 complex / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / p75NTR recruits signalling complexes / Downregulation of ERBB4 signaling / APC-Cdc20 mediated degradation of Nek2A / PINK1-PRKN Mediated Mitophagy / TRAF6-mediated induction of TAK1 complex within TLR4 complex / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / Pexophagy / Regulation of innate immune responses to cytosolic DNA / InlA-mediated entry of Listeria monocytogenes into host cells / VLDLR internalisation and degradation / Downregulation of ERBB2:ERBB3 signaling / NF-kB is activated and signals survival / NRIF signals cell death from the nucleus / Regulation of PTEN localization / Activated NOTCH1 Transmits Signal to the Nucleus / Regulation of BACH1 activity / Translesion synthesis by REV1 / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Translesion synthesis by POLK / MAP3K8 (TPL2)-dependent MAPK1/3 activation / TICAM1, RIP1-mediated IKK complex recruitment / Downregulation of TGF-beta receptor signaling / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Translesion synthesis by POLI / Gap-filling DNA repair synthesis and ligation in GG-NER / Josephin domain DUBs / Regulation of activated PAK-2p34 by proteasome mediated degradation / InlB-mediated entry of Listeria monocytogenes into host cell / IKK complex recruitment mediated by RIP1 / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / thymus development / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Autodegradation of Cdh1 by Cdh1:APC/C / TNFR1-induced NF-kappa-B signaling pathway / APC/C:Cdc20 mediated degradation of Securin / Asymmetric localization of PCP proteins / TCF dependent signaling in response to WNT / SCF-beta-TrCP mediated degradation of Emi1 / AUF1 (hnRNP D0) binds and destabilizes mRNA / NIK-->noncanonical NF-kB signaling / Ubiquitin-dependent degradation of Cyclin D / Regulation of NF-kappa B signaling / TNFR2 non-canonical NF-kB pathway / activated TAK1 mediates p38 MAPK activation / Assembly of the pre-replicative complex Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) / Xenopus laevis (African clawed frog) / synthetic construct (others) | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.2 Å | ||||||||||||
Authors | Thomas JF / Valencia-Sanchez MI / Armache K-J | ||||||||||||
Funding support | United States, 3 items
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Citation | Journal: Sci Adv / Year: 2023 Title: Structural basis of histone H2A lysine 119 deubiquitination by Polycomb repressive deubiquitinase BAP1/ASXL1. Authors: Jonathan F Thomas / Marco Igor Valencia-Sánchez / Simone Tamburri / Susan L Gloor / Samantha Rustichelli / Victoria Godínez-López / Pablo De Ioannes / Rachel Lee / Stephen Abini-Agbomson ...Authors: Jonathan F Thomas / Marco Igor Valencia-Sánchez / Simone Tamburri / Susan L Gloor / Samantha Rustichelli / Victoria Godínez-López / Pablo De Ioannes / Rachel Lee / Stephen Abini-Agbomson / Kristjan Gretarsson / Jonathan M Burg / Allison R Hickman / Lu Sun / Saarang Gopinath / Hailey F Taylor / Zu-Wen Sun / Ryan J Ezell / Anup Vaidya / Matthew J Meiners / Marcus A Cheek / William J Rice / Vladimir Svetlov / Evgeny Nudler / Chao Lu / Michael-Christopher Keogh / Diego Pasini / Karim-Jean Armache / Abstract: Histone H2A lysine 119 (H2AK119Ub) is monoubiquitinated by Polycomb repressive complex 1 and deubiquitinated by Polycomb repressive deubiquitinase complex (PR-DUB). PR-DUB cleaves H2AK119Ub to ...Histone H2A lysine 119 (H2AK119Ub) is monoubiquitinated by Polycomb repressive complex 1 and deubiquitinated by Polycomb repressive deubiquitinase complex (PR-DUB). PR-DUB cleaves H2AK119Ub to restrict focal H2AK119Ub at Polycomb target sites and to protect active genes from aberrant silencing. The PR-DUB subunits (BAP1 and ASXL1) are among the most frequently mutated epigenetic factors in human cancers. How PR-DUB establishes specificity for H2AK119Ub over other nucleosomal ubiquitination sites and how disease-associated mutations of the enzyme affect activity are unclear. Here, we determine a cryo-EM structure of human BAP1 and the ASXL1 DEUBAD in complex with a H2AK119Ub nucleosome. Our structural, biochemical, and cellular data reveal the molecular interactions of BAP1 and ASXL1 with histones and DNA that are critical for restructuring the nucleosome and thus establishing specificity for H2AK119Ub. These results further provide a molecular explanation for how >50 mutations in BAP1 and ASXL1 found in cancer can dysregulate H2AK119Ub deubiquitination, providing insight into understanding cancer etiology. | ||||||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_40789.map.gz | 53 MB | EMDB map data format | |
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Header (meta data) | emd-40789-v30.xml emd-40789.xml | 34.8 KB 34.8 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_40789_fsc.xml | 10.4 KB | Display | FSC data file |
Images | emd_40789.png | 165.1 KB | ||
Masks | emd_40789_msk_1.map | 103 MB | Mask map | |
Filedesc metadata | emd-40789.cif.gz | 9.4 KB | ||
Others | emd_40789_additional_1.map.gz emd_40789_additional_2.map.gz emd_40789_half_map_1.map.gz emd_40789_half_map_2.map.gz | 25.6 MB 96.5 MB 95.5 MB 95.5 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-40789 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-40789 | HTTPS FTP |
-Validation report
Summary document | emd_40789_validation.pdf.gz | 1016.8 KB | Display | EMDB validaton report |
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Full document | emd_40789_full_validation.pdf.gz | 1016.4 KB | Display | |
Data in XML | emd_40789_validation.xml.gz | 18.5 KB | Display | |
Data in CIF | emd_40789_validation.cif.gz | 23.8 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40789 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40789 | HTTPS FTP |
-Related structure data
Related structure data | 8svfMC C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_40789.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Sharpened map DNA clamp BAP1/ASXL1-H2AK119Ub nucleosome complex | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.05375 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_40789_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Additional map: Unsharpened map DNA clamp BAP1/ASXL1-H2AK119Ub nucleosome complex
File | emd_40789_additional_1.map | ||||||||||||
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Annotation | Unsharpened map DNA clamp BAP1/ASXL1-H2AK119Ub nucleosome complex | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Sharpened map Bfactor -63 DNA clamp BAP1/ASXL1-H2AK119Ub nucleosome...
File | emd_40789_additional_2.map | ||||||||||||
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Annotation | Sharpened map Bfactor -63 DNA clamp BAP1/ASXL1-H2AK119Ub nucleosome complex | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half-map B DNA clamp BAP1/ASXL1-H2AK119Ub nucleosome complex
File | emd_40789_half_map_1.map | ||||||||||||
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Annotation | Half-map B DNA clamp BAP1/ASXL1-H2AK119Ub nucleosome complex | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half-map A DNA clamp BAP1/ASXL1-H2AK119Ub nucleosome complex
File | emd_40789_half_map_2.map | ||||||||||||
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Annotation | Half-map A DNA clamp BAP1/ASXL1-H2AK119Ub nucleosome complex | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
+Entire : BAP1/ASXL1 bound to the H2AK119Ub Nucleosome
+Supramolecule #1: BAP1/ASXL1 bound to the H2AK119Ub Nucleosome
+Macromolecule #1: Histone H3.2
+Macromolecule #2: Histone H4
+Macromolecule #3: Histone H2A type 1
+Macromolecule #4: Histone H2B 1.1
+Macromolecule #7: Ubiquitin carboxyl-terminal hydrolase BAP1
+Macromolecule #8: Polycomb group protein ASXL1
+Macromolecule #9: Ubiquitin
+Macromolecule #5: DNA/RNA (187-MER)
+Macromolecule #6: DNA/RNA (327-MER)
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.1 mg/mL |
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Buffer | pH: 7.5 |
Grid | Model: Quantifoil / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 57.12 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.9000000000000001 µm / Nominal defocus min: 0.9 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+Image processing
-Atomic model buiding 1
Initial model |
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Refinement | Space: REAL | ||||||||||||||||||
Output model | PDB-8svf: |