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- PDB-8svf: BAP1/ASXL1 bound to the H2AK119Ub Nucleosome -

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Basic information

Entry
Database: PDB / ID: 8svf
TitleBAP1/ASXL1 bound to the H2AK119Ub Nucleosome
Components
  • DNA/RNA (187-MER)
  • DNA/RNA (327-MER)
  • Histone H2A type 1
  • Histone H2B 1.1
  • Histone H3.2
  • Histone H4
  • Polycomb group protein ASXL1Polycomb-group proteins
  • Ubiquitin carboxyl-terminal hydrolase BAP1
  • Ubiquitin
KeywordsNUCLEAR PROTEIN/DNA/RNA / 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 / response to inorganic substance / 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 / Constitutive Signaling by NOTCH1 HD Domain Mutants / Endosomal Sorting Complex Required For Transport (ESCRT) / NOTCH2 Activation and Transmission of Signal to the Nucleus / 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 / Regulation of FZD by ubiquitination / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Downregulation of ERBB4 signaling / p75NTR recruits signalling complexes / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / APC-Cdc20 mediated degradation of Nek2A / PINK1-PRKN Mediated Mitophagy / TRAF6-mediated induction of TAK1 complex within TLR4 complex / InlA-mediated entry of Listeria monocytogenes into host cells / Pexophagy / Regulation of innate immune responses to cytosolic DNA / VLDLR internalisation and degradation / Downregulation of ERBB2:ERBB3 signaling / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / Translesion synthesis by REV1 / NF-kB is activated and signals survival / Regulation of PTEN localization / Translesion synthesis by POLK / Regulation of BACH1 activity / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Translesion synthesis by POLI / Gap-filling DNA repair synthesis and ligation in GG-NER / MAP3K8 (TPL2)-dependent MAPK1/3 activation / TICAM1, RIP1-mediated IKK complex recruitment / Downregulation of TGF-beta receptor signaling / Josephin domain DUBs / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / 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 / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / thymus development / 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 / Regulation of NF-kappa B signaling / NIK-->noncanonical NF-kB signaling / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / Negative regulators of DDX58/IFIH1 signaling / TNFR2 non-canonical NF-kB pathway / NOTCH3 Activation and Transmission of Signal to the Nucleus
Similarity search - Function
Polycomb protein ASX/ASX-like / Protein ASX-like, PHD domain / ASX, DEUBAD domain / Asx homology domain / PHD domain of transcriptional enhancer, Asx / ASXL, HARE-HTH domain / HB1, ASXL, restriction endonuclease HTH domain / HARE-type HTH domain profile. / Peptidase C12, C-terminal domain / Ubiquitin carboxyl-terminal hydrolases ...Polycomb protein ASX/ASX-like / Protein ASX-like, PHD domain / ASX, DEUBAD domain / Asx homology domain / PHD domain of transcriptional enhancer, Asx / ASXL, HARE-HTH domain / HB1, ASXL, restriction endonuclease HTH domain / HARE-type HTH domain profile. / Peptidase C12, C-terminal domain / Ubiquitin carboxyl-terminal hydrolases / DEUBAD domain / DEUBAD (DEUBiquitinase ADaptor) domain profile. / Peptidase C12, ubiquitin carboxyl-terminal hydrolase superfamily / Ubiquitin carboxyl-terminal hydrolase, family 1 / Peptidase C12, ubiquitin carboxyl-terminal hydrolase / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site / Histone H2A signature. / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone H2A / Histone 2A / Histone H4, conserved site / Histone H4 signature. / Histone H4 / Histone H4 / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / Papain-like cysteine peptidase superfamily / Histone H3 signature 1. / Ubiquitin conserved site / Ubiquitin domain / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Ubiquitin domain signature. / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Histone-fold / Ubiquitin family / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
DNA/RNA hybrid / DNA/RNA hybrid (> 10) / DNA/RNA hybrid (> 100) / Histone H2B 1.1 / Histone H2A type 1 / Polyubiquitin-C / Histone H4 / Histone H3.2 / Polycomb group protein ASXL1 / Ubiquitin carboxyl-terminal hydrolase BAP1
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
Homo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsThomas, J.F. / Valencia-Sanchez, M.I. / Armache, K.-J.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM115882 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA266978 United States
The Mark Foundation United States
CitationJournal: 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
DepositionMay 16, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 30, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 14, 2024Group: Refinement description / Source and taxonomy / Category: em_3d_fitting_list / entity_src_gen
Item: _em_3d_fitting_list.initial_refinement_model_id / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id ..._em_3d_fitting_list.initial_refinement_model_id / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone H3.2
B: Histone H4
C: Histone H2A type 1
D: Histone H2B 1.1
E: Histone H3.2
F: Histone H4
G: Histone H2A type 1
H: Histone H2B 1.1
I: DNA/RNA (187-MER)
J: DNA/RNA (327-MER)
K: Ubiquitin carboxyl-terminal hydrolase BAP1
L: Polycomb group protein ASXL1
M: Ubiquitin


Theoretical massNumber of molelcules
Total (without water)525,92413
Polymers525,92413
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 7 types, 11 molecules AEBFCGDHKLM

#1: Protein Histone H3.2 / Histone H3


Mass: 15435.126 Da / Num. of mol.: 2 / Mutation: G103A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli) / References: UniProt: P84233
#2: Protein Histone H4 /


Mass: 11394.426 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli) / References: UniProt: P62799
#3: Protein Histone H2A type 1


Mass: 14093.436 Da / Num. of mol.: 2 / Mutation: G100R, K120C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli) / References: UniProt: P06897
#4: Protein Histone H2B 1.1 / H2B1.1


Mass: 13979.291 Da / Num. of mol.: 2 / Mutation: S33T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli) / References: UniProt: P02281
#7: Protein Ubiquitin carboxyl-terminal hydrolase BAP1 / BRCA1-associated protein 1 / Cerebral protein 6


Mass: 80472.617 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BAP1, KIAA0272, hucep-6 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q92560, ubiquitinyl hydrolase 1
#8: Protein Polycomb group protein ASXL1 / Polycomb-group proteins / Additional sex combs-like protein 1


Mass: 165635.203 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ASXL1, KIAA0978 / Production host: Escherichia coli (E. coli) / References: UniProt: Q8IXJ9
#9: Protein Ubiquitin /


Mass: 8576.831 Da / Num. of mol.: 1 / Mutation: G76C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBC / Production host: Escherichia coli (E. coli) / References: UniProt: P0CG48

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DNA/RNA hybrid , 2 types, 2 molecules IJ

#5: DNA/RNA hybrid DNA/RNA (187-MER)


Mass: 58568.770 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: DNA/RNA hybrid DNA/RNA (327-MER)


Mass: 102866.516 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: BAP1/ASXL1 bound to the H2AK119Ub Nucleosome / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Xenopus laevis (African clawed frog)8355
41Escherichia coli (E. coli)562
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Spodoptera frugiperda (fall armyworm)7108
31Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1900 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 57.12 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.1.1particle selection
2Leginonimage acquisition
7UCSF Chimera1.14model fitting
8Coot0.9.8.7model fitting
12cryoSPARC4.1.1classification
13cryoSPARC4.1.13D reconstruction
20PHENIX1.20.1model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 39056 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Atomic model building

3D fitting-ID: 1

IDPDB-IDDetailsSource nameTypeAccession codeInitial refinement model-ID
1Multimer predictionAlphaFoldin silico model
23tu4

3tu4

PDBexperimental model3tu42
3SwissModel templateOtherintegrative model4uel3
4SwissModel templateOtherintegrative model6hgc4
57k5y

7k5y

PDBexperimental model7k5y5
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00716757
ELECTRON MICROSCOPYf_angle_d0.63523947
ELECTRON MICROSCOPYf_dihedral_angle_d25.6776765
ELECTRON MICROSCOPYf_chiral_restr0.042707
ELECTRON MICROSCOPYf_plane_restr0.0041994

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