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- PDB-8h1t: Cryo-EM structure of BAP1-ASXL1 bound to chromatosome -

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Entry
Database: PDB / ID: 8h1t
TitleCryo-EM structure of BAP1-ASXL1 bound to chromatosome
Components
  • (DNA (187-MER)) x 2
  • Histone H1.4
  • Histone H2A type 1-D
  • Histone H2B type 2-E
  • Histone H3.1
  • Histone H4
  • Polycomb group protein ASXL1
  • Ubiquitin
  • Ubiquitin carboxyl-terminal hydrolase BAP1
KeywordsGENE REGULATION / nucleosome / histone deubiquitination / chromatin
Function / homology
Function and homology information


thrombocyte differentiation / nucleate erythrocyte differentiation / PR-DUB complex / platelet morphogenesis / histone H2A deubiquitinase activity / positive regulation of retinoic acid receptor signaling pathway / lung saccule development / macrophage homeostasis / leukocyte proliferation / podocyte development ...thrombocyte differentiation / nucleate erythrocyte differentiation / PR-DUB complex / platelet morphogenesis / histone H2A deubiquitinase activity / positive regulation of retinoic acid receptor signaling pathway / lung saccule development / macrophage homeostasis / leukocyte proliferation / podocyte development / negative regulation of peroxisome proliferator activated receptor signaling pathway / myeloid cell apoptotic process / neutrophil differentiation / regulation of kidney size / hematopoietic stem cell homeostasis / common myeloid progenitor cell proliferation / monoubiquitinated protein deubiquitination / tissue homeostasis / protein K48-linked deubiquitination / negative regulation of DNA recombination / nuclear retinoic acid receptor binding / Apoptosis induced DNA fragmentation / peroxisome proliferator activated receptor binding / chromosome condensation / hypothalamus gonadotrophin-releasing hormone neuron development / bone marrow development / female meiosis I / positive regulation of protein monoubiquitination / positive regulation of protein targeting to mitochondrion / fat pad development / mitochondrion transport along microtubule / nucleosomal DNA binding / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / erythrocyte maturation / female gonad development / negative regulation of fat cell differentiation / seminiferous tubule development / regulation of cytokine production involved in inflammatory response / male meiosis I / hemopoiesis / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / homeostasis of number of cells / protein deubiquitination / response to retinoic acid / heart morphogenesis / heterochromatin / negative regulation of megakaryocyte differentiation / protein localization to CENP-A containing chromatin / energy homeostasis / Chromatin modifying enzymes / Replacement of protamines by nucleosomes in the male pronucleus / regulation of neuron apoptotic process / CENP-A containing nucleosome / neuron projection morphogenesis / Packaging Of Telomere Ends / regulation of proteasomal protein catabolic process / Maturation of protein E / Maturation of protein E / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / 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 / Endosomal Sorting Complex Required For Transport (ESCRT) / Membrane binding and targetting of GAG proteins / Negative regulation of FLT3 / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / Constitutive Signaling by NOTCH1 HD Domain Mutants / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1,TRAF6-dependent induction of TAK1 complex / Deposition of new CENPA-containing nucleosomes at the centromere / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Downregulation of ERBB4 signaling / Regulation of FZD by ubiquitination / APC-Cdc20 mediated degradation of Nek2A / p75NTR recruits signalling complexes / telomere organization / InlA-mediated entry of Listeria monocytogenes into host cells / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Interleukin-7 signaling / Regulation of pyruvate metabolism / NF-kB is activated and signals survival / Inhibition of DNA recombination at telomere / Regulation of innate immune responses to cytosolic DNA / Downregulation of ERBB2:ERBB3 signaling / RNA Polymerase I Promoter Opening / Pexophagy
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 / UCH37-like (ULD) domain profile. / Peptidase C12, C-terminal domain / Ubiquitin carboxyl-terminal hydrolases / ASXL, HARE-HTH domain / HB1, ASXL, restriction endonuclease HTH domain ...Polycomb protein ASX/ASX-like / Protein ASX-like, PHD domain / ASX, DEUBAD domain / Asx homology domain / PHD domain of transcriptional enhancer, Asx / UCH37-like (ULD) domain profile. / Peptidase C12, C-terminal domain / Ubiquitin carboxyl-terminal hydrolases / ASXL, HARE-HTH domain / HB1, ASXL, restriction endonuclease HTH domain / HARE-type HTH domain profile. / DEUBAD domain / DEUBAD (DEUBiquitinase ADaptor) domain profile. / Peptidase C12, ubiquitin carboxyl-terminal hydrolase superfamily / Ubiquitin carboxyl-terminal hydrolase, family 1 / Ubiquitin carboxyl-terminal hydrolase (UCH) catalytic domain profile. / Peptidase C12, ubiquitin carboxyl-terminal hydrolase / Linker histone H1/H5 / linker histone H1 and H5 family / Linker histone H1/H5, domain H15 / Linker histone H1/H5 globular (H15) domain profile. / Domain in histone families 1 and 5 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / Papain-like cysteine peptidase superfamily / : / Histone H2B signature. / Histone H2A conserved site / Histone H2A signature. / Histone H2B / Histone H2B / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone 2A / Histone H2A / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / Histone H4, conserved site / Histone H4 signature. / Histone H4 / Histone H4 / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / Histone H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / : / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 domain / Ubiquitin-like (UB roll) / Histone-fold / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily / Roll / Alpha Beta
Similarity search - Domain/homology
DNA / DNA (> 10) / DNA (> 100) / Polyubiquitin-B / Histone H1.4 / Histone H2A type 1-D / Histone H4 / Histone H3.1 / Histone H2B type 2-E / Polycomb group protein ASXL1 / Ubiquitin carboxyl-terminal hydrolase BAP1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsGe, W. / Yu, C. / Xu, R.M.
Funding support China, 4items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2019YFA0508900 China
National Natural Science Foundation of China (NSFC)31991162 China
National Natural Science Foundation of China (NSFC)918532204 China
National Natural Science Foundation of China (NSFC)92153302 China
CitationJournal: Nature / Year: 2023
Title: Basis of the H2AK119 specificity of the Polycomb repressive deubiquitinase.
Authors: Weiran Ge / Cong Yu / Jingjing Li / Zhenyu Yu / Xiaorong Li / Yan Zhang / Chao-Pei Liu / Yingfeng Li / Changlin Tian / Xinzheng Zhang / Guohong Li / Bing Zhu / Rui-Ming Xu /
Abstract: Repression of gene expression by protein complexes of the Polycomb group is a fundamental mechanism that governs embryonic development and cell-type specification. The Polycomb repressive ...Repression of gene expression by protein complexes of the Polycomb group is a fundamental mechanism that governs embryonic development and cell-type specification. The Polycomb repressive deubiquitinase (PR-DUB) complex removes the ubiquitin moiety from monoubiquitinated histone H2A K119 (H2AK119ub1) on the nucleosome, counteracting the ubiquitin E3 ligase activity of Polycomb repressive complex 1 (PRC1) to facilitate the correct silencing of genes by Polycomb proteins and safeguard active genes from inadvertent silencing by PRC1 (refs. ). The intricate biological function of PR-DUB requires accurate targeting of H2AK119ub1, but PR-DUB can deubiquitinate monoubiquitinated free histones and peptide substrates indiscriminately; the basis for its exquisite nucleosome-dependent substrate specificity therefore remains unclear. Here we report the cryo-electron microscopy structure of human PR-DUB, composed of BAP1 and ASXL1, in complex with the chromatosome. We find that ASXL1 directs the binding of the positively charged C-terminal extension of BAP1 to nucleosomal DNA and histones H3-H4 near the dyad, an addition to its role in forming the ubiquitin-binding cleft. Furthermore, a conserved loop segment of the catalytic domain of BAP1 is situated near the H2A-H2B acidic patch. This distinct nucleosome-binding mode displaces the C-terminal tail of H2A from the nucleosome surface, and endows PR-DUB with the specificity for H2AK119ub1.
History
DepositionOct 4, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 1, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 12, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Apr 19, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jul 3, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone H3.1
B: Histone H4
C: Histone H2A type 1-D
D: Histone H2B type 2-E
E: Histone H3.1
F: Histone H4
G: Histone H2A type 1-D
H: Histone H2B type 2-E
I: DNA (187-MER)
J: DNA (187-MER)
K: Histone H1.4
L: Ubiquitin carboxyl-terminal hydrolase BAP1
M: Ubiquitin
N: Polycomb group protein ASXL1


Theoretical massNumber of molelcules
Total (without water)379,32314
Polymers379,32314
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 8 types, 12 molecules AEBFCGDHKLMN

#1: Protein Histone H3.1


Mass: 15437.167 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: P68431
#2: Protein Histone H4


Mass: 11394.426 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: P62805
#3: Protein Histone H2A type 1-D / Histone H2A.3 / Histone H2A/g


Mass: 14137.537 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: H2AC7, H2AFG, HIST1H2AD / Production host: Escherichia coli (E. coli) / References: UniProt: P20671
#4: Protein Histone H2B type 2-E / Histone H2B-GL105 / Histone H2B.q / H2B/q


Mass: 13951.239 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HIST2H2BE, H2BFQ / Production host: Escherichia coli (E. coli) / References: UniProt: Q16778
#7: Protein Histone H1.4 / Histone H1b / Histone H1s-4


Mass: 23190.926 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: H1-4, H1F4, HIST1H1E / Production host: Escherichia coli (E. coli) / References: UniProt: P10412
#8: Protein Ubiquitin carboxyl-terminal hydrolase BAP1 / BRCA1-associated protein 1 / Cerebral protein 6


Mass: 80456.555 Da / Num. of mol.: 1 / Mutation: C91S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BAP1, KIAA0272, hucep-6 / Production host: Escherichia coli (E. coli) / References: UniProt: Q92560, ubiquitinyl hydrolase 1
#9: Protein Ubiquitin


Mass: 8576.831 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli (E. coli) / References: UniProt: P0CG47
#10: Protein Polycomb group protein ASXL1 / Additional sex combs-like protein 1


Mass: 41788.602 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

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DNA chain , 2 types, 2 molecules IJ

#5: DNA chain DNA (187-MER)


Mass: 57438.527 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#6: DNA chain DNA (187-MER)


Mass: 58030.969 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)

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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: Cryo-EM structure of BAP1-ASXL1 bound to chromatosome / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 284 K

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20_4444: / Classification: refinement
EM software
IDNameVersionCategory
2SerialEMimage acquisition
4cryoSPARC3.2CTF correction
7UCSF Chimera1.14model fitting
12cryoSPARC3.23D reconstruction
13RELION3.0.83D reconstruction
14PHENIX1.2model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 95225 / Symmetry type: POINT
Atomic model buildingSpace: REAL
RefinementHighest resolution: 3 Å
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00218395
ELECTRON MICROSCOPYf_angle_d0.46626279
ELECTRON MICROSCOPYf_dihedral_angle_d23.4387520
ELECTRON MICROSCOPYf_chiral_restr0.0322995
ELECTRON MICROSCOPYf_plane_restr0.0032176

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