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- PDB-6kiw: Cryo-EM structure of human MLL3-ubNCP complex (4.0 angstrom) -

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Entry
Database: PDB / ID: 6kiw
TitleCryo-EM structure of human MLL3-ubNCP complex (4.0 angstrom)
Components
  • DNA (144-MER)
  • DNA (145-MER)
  • Histone H2A
  • Histone H2B 1.1
  • Histone H3
  • Histone H4
  • Histone-lysine N-methyltransferase 2C
  • Retinoblastoma-binding protein 5
  • Set1/Ash2 histone methyltransferase complex subunit ASH2
  • Ubiquitin
  • WD repeat-containing protein 5
KeywordsTRANSCRIPTION/DNA / histone modification / nucleosome / MLL / TRANSCRIPTION / TRANSCRIPTION-DNA complex
Function / homology
Function and homology information


[histone H3]-lysine4 N-methyltransferase / histone H3K4 monomethyltransferase activity / histone H3K4 trimethyltransferase activity / Epigenetic regulation of gene expression by MLL3 and MLL4 complexes / MLL3/4 complex / Set1C/COMPASS complex / MLL1/2 complex / ATAC complex / NSL complex / histone H3K4 methyltransferase activity ...[histone H3]-lysine4 N-methyltransferase / histone H3K4 monomethyltransferase activity / histone H3K4 trimethyltransferase activity / Epigenetic regulation of gene expression by MLL3 and MLL4 complexes / MLL3/4 complex / Set1C/COMPASS complex / MLL1/2 complex / ATAC complex / NSL complex / histone H3K4 methyltransferase activity / Cardiogenesis / Formation of the ternary complex, and subsequently, the 43S complex / acyltransferase activity / histone methyltransferase complex / Ribosomal scanning and start codon recognition / histone methyltransferase activity / Translation initiation complex formation / Formation of WDR5-containing histone-modifying complexes / hemopoiesis / SARS-CoV-1 modulates host translation machinery / regulation of cell division / Peptide chain elongation / regulation of embryonic development / MLL1 complex / Selenocysteine synthesis / Formation of a pool of free 40S subunits / histone acetyltransferase complex / Eukaryotic Translation Termination / Response of EIF2AK4 (GCN2) to amino acid deficiency / SRP-dependent cotranslational protein targeting to membrane / Viral mRNA Translation / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / GTP hydrolysis and joining of the 60S ribosomal subunit / L13a-mediated translational silencing of Ceruloplasmin expression / Major pathway of rRNA processing in the nucleolus and cytosol / response to electrical stimulus / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / : / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / cytosolic ribosome / 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 / positive regulation of gluconeogenesis / 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) / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / Negative regulation of FLT3 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / Constitutive Signaling by NOTCH1 HD Domain Mutants / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Regulation of FZD by ubiquitination / Downregulation of ERBB4 signaling / p75NTR recruits signalling complexes / APC-Cdc20 mediated degradation of Nek2A / 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 / Regulation of pyruvate metabolism / Regulation of innate immune responses to cytosolic DNA / transcription initiation-coupled chromatin remodeling / NF-kB is activated and signals survival / Downregulation of ERBB2:ERBB3 signaling / Pexophagy / NRIF signals cell death from the nucleus / VLDLR internalisation and degradation / Regulation of PTEN localization / Activated NOTCH1 Transmits Signal to the Nucleus / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / TICAM1, RIP1-mediated IKK complex recruitment / Translesion synthesis by REV1 / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Translesion synthesis by POLK / InlB-mediated entry of Listeria monocytogenes into host cell / Downregulation of TGF-beta receptor signaling / Josephin domain DUBs / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / Regulation of activated PAK-2p34 by proteasome mediated degradation / Translesion synthesis by POLI / IKK complex recruitment mediated by RIP1 / Gap-filling DNA repair synthesis and ligation in GG-NER / PINK1-PRKN Mediated Mitophagy / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / gluconeogenesis / TNFR1-induced NF-kappa-B signaling pathway / skeletal system development
Similarity search - Function
Histone-lysine N-methyltransferase 2C / KMT2C, ePHD1 / KMT2C, ePHD2 / : / : / : / DHHC domain profile. / HMG-I/HMG-Y, DNA-binding, conserved site / HMG-I and HMG-Y DNA-binding domain (A+T-hook). / : ...Histone-lysine N-methyltransferase 2C / KMT2C, ePHD1 / KMT2C, ePHD2 / : / : / : / DHHC domain profile. / HMG-I/HMG-Y, DNA-binding, conserved site / HMG-I and HMG-Y DNA-binding domain (A+T-hook). / : / : / Set1/Ash2 histone methyltransferase complex subunit ASH2-like, WH / ASH2, PHD zinc finger / Histone methyltransferase complex subunit ASH2 / Retinoblastoma-binding protein 5/Swd1 / SPRY domain / FY-rich, N-terminal / F/Y-rich N-terminus / PHD-like zinc-binding domain / FYR domain FYRN motif profile. / "FY-rich" domain, N-terminal region / FY-rich, C-terminal / F/Y rich C-terminus / FYR domain FYRC motif profile. / "FY-rich" domain, C-terminal region / Beta-clip-like / SET domain / Cysteine-rich motif following a subset of SET domains / Post-SET domain / Post-SET domain profile. / high mobility group / High mobility group box domain / High mobility group box domain superfamily / Histone, subunit A / Histone, subunit A / PHD-zinc-finger like domain / Extended PHD (ePHD) domain / Extended PHD (ePHD) domain profile. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain / SET domain superfamily / SET domain profile. / SET domain / SPRY domain / B30.2/SPRY domain / B30.2/SPRY domain profile. / B30.2/SPRY domain superfamily / Domain in SPla and the RYanodine Receptor. / SPRY domain / S27a-like superfamily / Ribosomal protein S27a / Ribosomal protein S27a / Ribosomal protein S27a / PHD-finger / Zinc finger PHD-type signature. / Ring finger / YVTN repeat-like/Quinoprotein amine dehydrogenase / : / Histone H2B signature. / Histone H2B / Histone H2B / Zinc finger PHD-type profile. / Histone H2A conserved site / Histone H2A signature. / Histone H2A, C-terminal domain / C-terminus of histone H2A / Beta Complex / 7 Propeller / Methylamine Dehydrogenase; Chain H / Histone H2A / Histone 2A / Zinc finger, PHD-finger / 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 / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, FYVE/PHD-type / Histone H3 signature 1. / Zinc finger RING-type profile. / Zinc finger, RING-type / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / : / Ubiquitin domain signature. / Histone H2A/H2B/H3 / Ubiquitin conserved site / Core histone H2A/H2B/H3/H4 / Ubiquitin domain / Histone-fold / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain
Similarity search - Domain/homology
DNA / DNA (> 10) / DNA (> 100) / Histone H3 / Histone H2B 1.1 / Histone H2A type 1 / WD repeat-containing protein 5 / Histone H4 / Ubiquitin-ribosomal protein eS31 fusion protein / Histone H3.2 ...DNA / DNA (> 10) / DNA (> 100) / Histone H3 / Histone H2B 1.1 / Histone H2A type 1 / WD repeat-containing protein 5 / Histone H4 / Ubiquitin-ribosomal protein eS31 fusion protein / Histone H3.2 / Retinoblastoma-binding protein 5 / Histone H2A / Histone-lysine N-methyltransferase 2C / Set1/Ash2 histone methyltransferase complex subunit ASH2
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
Homo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsHuang, J. / Xue, H. / Yao, T.
Funding support China, 1items
OrganizationGrant numberCountry
National Science Foundation (China) China
CitationJournal: Nature / Year: 2019
Title: Structural basis of nucleosome recognition and modification by MLL methyltransferases.
Authors: Han Xue / Tonghui Yao / Mi Cao / Guanjun Zhu / Yan Li / Guiyong Yuan / Yong Chen / Ming Lei / Jing Huang /
Abstract: Methyltransferases of the mixed-lineage leukaemia (MLL) family-which include MLL1, MLL2, MLL3, MLL4, SET1A and SET1B-implement methylation of histone H3 on lysine 4 (H3K4), and have critical and ...Methyltransferases of the mixed-lineage leukaemia (MLL) family-which include MLL1, MLL2, MLL3, MLL4, SET1A and SET1B-implement methylation of histone H3 on lysine 4 (H3K4), and have critical and distinct roles in the regulation of transcription in haematopoiesis, adipogenesis and development. The C-terminal catalytic SET (Su(var.)3-9, enhancer of zeste and trithorax) domains of MLL proteins are associated with a common set of regulatory factors (WDR5, RBBP5, ASH2L and DPY30) to achieve specific activities. Current knowledge of the regulation of MLL activity is limited to the catalysis of histone H3 peptides, and how H3K4 methyl marks are deposited on nucleosomes is poorly understood. H3K4 methylation is stimulated by mono-ubiquitination of histone H2B on lysine 120 (H2BK120ub1), a prevalent histone H2B mark that disrupts chromatin compaction and favours open chromatin structures, but the underlying mechanism remains unknown. Here we report cryo-electron microscopy structures of human MLL1 and MLL3 catalytic modules associated with nucleosome core particles that contain H2BK120ub1 or unmodified H2BK120. These structures demonstrate that the MLL1 and MLL3 complexes both make extensive contacts with the histone-fold and DNA regions of the nucleosome; this allows ease of access to the histone H3 tail, which is essential for the efficient methylation of H3K4. The H2B-conjugated ubiquitin binds directly to RBBP5, orienting the association between MLL1 or MLL3 and the nucleosome. The MLL1 and MLL3 complexes display different structural organizations at the interface between the WDR5, RBBP5 and MLL1 (or the corresponding MLL3) subunits, which accounts for the opposite roles of WDR5 in regulating the activity of the two enzymes. These findings transform our understanding of the structural basis for the regulation of MLL activity at the nucleosome level, and highlight the pivotal role of nucleosome regulation in histone-tail modification.
History
DepositionJul 20, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 11, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 18, 2019Group: Data collection / Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 2, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Nov 6, 2019Group: Data collection / Other / Category: cell / Item: _cell.Z_PDB
Revision 1.4Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Histone H3
B: Histone H4
C: Histone H2A
D: Histone H2B 1.1
E: Histone H3
F: Histone H4
G: Histone H2A
H: Histone H2B 1.1
I: DNA (144-MER)
J: DNA (145-MER)
K: Histone-lysine N-methyltransferase 2C
N: Retinoblastoma-binding protein 5
O: Ubiquitin
R: WD repeat-containing protein 5
T: Set1/Ash2 histone methyltransferase complex subunit ASH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)385,77716
Polymers385,71215
Non-polymers651
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: cross-linking
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 9 types, 13 molecules AEBFCGDHKNORT

#1: Protein Histone H3


Mass: 15303.930 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: XELAEV_18002543mg / Production host: Escherichia coli (E. coli) / References: UniProt: A0A310TTQ1, UniProt: P84233*PLUS
#2: Protein Histone H4


Mass: 11263.231 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


Mass: 13978.241 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: hist1h2aj, LOC494591, XELAEV_18003602mg / Production host: Escherichia coli (E. coli) / References: UniProt: Q6AZJ8, UniProt: P06897*PLUS
#4: Protein Histone H2B 1.1 / H2B1.1


Mass: 13498.715 Da / Num. of mol.: 2 / Mutation: S29T/K117C
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 Histone-lysine N-methyltransferase 2C / Lysine N-methyltransferase 2C / Homologous to ALR protein / Myeloid/lymphoid or mixed-lineage ...Lysine N-methyltransferase 2C / Homologous to ALR protein / Myeloid/lymphoid or mixed-lineage leukemia protein 3


Mass: 23642.941 Da / Num. of mol.: 1 / Mutation: C4708S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KMT2C, HALR, KIAA1506, MLL3 / Production host: Escherichia coli (E. coli)
References: UniProt: Q8NEZ4, histone-lysine N-methyltransferase
#8: Protein Retinoblastoma-binding protein 5 / RBBP-5 / Retinoblastoma-binding protein RBQ-3


Mass: 59223.477 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RBBP5, RBQ3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15291
#9: Protein Ubiquitin


Mass: 8622.922 Da / Num. of mol.: 1 / Mutation: G76C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RPS27A, UBA80, UBCEP1 / Production host: Escherichia coli (E. coli) / References: UniProt: P62979
#10: Protein WD repeat-containing protein 5 / BMP2-induced 3-kb gene protein


Mass: 36635.438 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR5, BIG3 / Production host: Escherichia coli (E. coli) / References: UniProt: P61964
#11: Protein Set1/Ash2 histone methyltransferase complex subunit ASH2 / ASH2-like protein


Mass: 60288.758 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ASH2L, ASH2L1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UBL3

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DNA chain , 2 types, 2 molecules IJ

#5: DNA chain DNA (144-MER)


Mass: 44217.172 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: DNA chain DNA (145-MER)


Mass: 44992.648 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 1 types, 1 molecules

#12: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn

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Details

Has ligand of interestN

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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

Component
IDNameTypeEntity IDParent-IDSource
1Human MLL3 complex associated with an H2B-monoubiquitinated nucleosome (4.0 angstrom)COMPLEX#1-#110MULTIPLE SOURCES
2Human MLL3COMPLEX#1-#111RECOMBINANT
3H2B-monoubiquitinated nucleosomeCOMPLEX#1-#111MULTIPLE SOURCES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Xenopus laevis (African clawed frog)8355
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli (E. coli)562
23Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.13_2998refinement
PHENIX1.13_2998refinement
CTF correctionType: PHASE FLIPPING ONLY
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 81945 / Symmetry type: POINT
RefinementStereochemistry target values: GeoStd + Monomer Library
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.005921207
ELECTRON MICROSCOPYf_angle_d0.864229905
ELECTRON MICROSCOPYf_chiral_restr0.05143371
ELECTRON MICROSCOPYf_plane_restr0.00682785
ELECTRON MICROSCOPYf_dihedral_angle_d19.043511726

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