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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


Recognition of DNA damage by PCNA-containing replication complex / Translesion Synthesis by POLH / Translesion synthesis by REV1 / Negative regulation of FGFR1 signaling / Activation of NF-kappaB in B cells / ISG15 antiviral mechanism / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / ER-Phagosome pathway / Downregulation of ERBB4 signaling ...Recognition of DNA damage by PCNA-containing replication complex / Translesion Synthesis by POLH / Translesion synthesis by REV1 / Negative regulation of FGFR1 signaling / Activation of NF-kappaB in B cells / ISG15 antiviral mechanism / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / ER-Phagosome pathway / Downregulation of ERBB4 signaling / Spry regulation of FGF signaling / Downregulation of ERBB2:ERBB3 signaling / L13a-mediated translational silencing of Ceruloplasmin expression / Peptide chain elongation / Budding and maturation of HIV virion / NOD1/2 Signaling Pathway / TICAM1, RIP1-mediated IKK complex recruitment / DDX58/IFIH1-mediated induction of interferon-alpha/beta / APC/C:Cdc20 mediated degradation of Cyclin B / SCF-beta-TrCP mediated degradation of Emi1 / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / AUF1 (hnRNP D0) binds and destabilizes mRNA / NOTCH2 Activation and Transmission of Signal to the Nucleus / Regulation of innate immune responses to cytosolic DNA / PKMTs methylate histone lysines / HATs acetylate histones / RMTs methylate histone arginines / Glycogen synthesis / Autodegradation of the E3 ubiquitin ligase COP1 / Deactivation of the beta-catenin transactivating complex / Myoclonic epilepsy of Lafora / ABC-family proteins mediated transport / Circadian Clock / TAK1 activates NFkB by phosphorylation and activation of IKKs complex / activated TAK1 mediates p38 MAPK activation / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / Asymmetric localization of PCP proteins / FCERI mediated NF-kB activation / Degradation of AXIN / Degradation of DVL / Regulation of FZD by ubiquitination / Pink/Parkin Mediated Mitophagy / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Regulation of TNFR1 signaling / TNFR1-induced NFkappaB signaling pathway / Hedgehog ligand biogenesis / Hh mutants that don't undergo autocatalytic processing are degraded by ERAD / Dectin-1 mediated noncanonical NF-kB signaling / CLEC7A (Dectin-1) signaling / Degradation of GLI1 by the proteasome / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD Domain Mutants / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / NRIF signals cell death from the nucleus / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Membrane binding and targetting of GAG proteins / Assembly Of The HIV Virion / APC-Cdc20 mediated degradation of Nek2A / SRP-dependent cotranslational protein targeting to membrane / Vpu mediated degradation of CD4 / Vif-mediated degradation of APOBEC3G / EGFR downregulation / SCF(Skp2)-mediated degradation of p27/p21 / Viral mRNA Translation / Degradation of beta-catenin by the destruction complex / TCF dependent signaling in response to WNT / Formation of the beta-catenin:TCF transactivating complex / Downstream TCR signaling / p75NTR recruits signalling complexes / Stimuli-sensing channels / Selenocysteine synthesis / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Regulation of PLK1 Activity at G2/M Transition / Oncogene Induced Senescence / Senescence-Associated Secretory Phenotype (SASP) / Oxidative Stress Induced Senescence / Separation of Sister Chromatids / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / NF-kB is activated and signals survival / Downregulation of SMAD2/3:SMAD4 transcriptional activity / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / Downregulation of TGF-beta receptor signaling / Activated NOTCH1 Transmits Signal to the Nucleus / NOTCH1 Intracellular Domain Regulates Transcription / Regulation of activated PAK-2p34 by proteasome mediated degradation / Hedgehog 'on' state / Formation of a pool of free 40S subunits / E3 ubiquitin ligases ubiquitinate target proteins / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Downregulation of ERBB2 signaling / Clathrin-mediated endocytosis / Cargo recognition for clathrin-mediated endocytosis / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / The role of GTSE1 in G2/M progression after G2 checkpoint / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Ubiquitin-dependent degradation of Cyclin D / Eukaryotic Translation Termination
Zinc finger PHD-type profile. / Ubiquitin domain profile. / Trp-Asp (WD) repeats profile. / Zinc finger RING-type profile. / B30.2/SPRY domain profile. / DHHC domain profile. / SET domain profile. / Trp-Asp (WD) repeats circular profile. / Post-SET domain profile. / FYR domain FYRN motif profile. ...Zinc finger PHD-type profile. / Ubiquitin domain profile. / Trp-Asp (WD) repeats profile. / Zinc finger RING-type profile. / B30.2/SPRY domain profile. / DHHC domain profile. / SET domain profile. / Trp-Asp (WD) repeats circular profile. / Post-SET domain profile. / FYR domain FYRN motif profile. / FYR domain FYRC motif profile. / Extended PHD (ePHD) domain profile. / Histone H3 signature 2. / Zinc finger PHD-type signature. / Trp-Asp (WD) repeats signature. / KMT2C, ePHD2 / G-protein beta WD-40 repeat / Ubiquitin-like domain superfamily / Histone H2A, C-terminal domain / Histone H2A conserved site / Extended PHD (ePHD) domain / CENP-T/Histone H4, histone fold / WD40-repeat-containing domain superfamily / High mobility group box domain superfamily / Histone methyltransferase complex subunit ASH2 / Retinoblastoma-binding protein 5/Swd1 / WD40-repeat-containing protein Swd3/WDR5 / Histone-lysine N-methyltransferase 2C / S27a-like superfamily / KMT2C, ePHD1 / Core histone H2A/H2B/H3/H4 / Histone H2B signature. / Centromere kinetochore component CENP-T histone fold / HMG-I and HMG-Y DNA-binding domain (A+T-hook). / Histone H3 signature 1. / Ubiquitin domain signature. / Histone H4 signature. / Histone H2A signature. / C-terminus of histone H2A / F/Y rich C-terminus / Ubiquitin family / F/Y-rich N-terminus / Ribosomal protein S27a / SET domain / PHD-finger / SPRY domain / WD domain, G-beta repeat / Ubiquitin conserved site / Ubiquitin domain / Histone H4, conserved site / Zinc finger, PHD-finger / Ribosomal protein S27a / Histone H3/CENP-A / Histone H2B / Ubiquitin-like domain / HMG-I/HMG-Y, DNA-binding, conserved site / SET domain / WD40 repeat / Zinc finger, RING-type / B30.2/SPRY domain / Histone H4 / Zinc finger, PHD-type / Histone H2A / Post-SET domain / SPRY domain / FY-rich, N-terminal / FY-rich, C-terminal / TATA box binding protein associated factor (TAF) / Histone H2A/H2B/H3 / High mobility group box domain / Histone-fold / Zinc finger, FYVE/PHD-type / Zinc-binding ribosomal protein / Zinc finger, RING/FYVE/PHD-type / Concanavalin A-like lectin/glucanase domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / WD40-repeat-containing domain / WD40 repeat, conserved site
Histone H3 / Histone H2B 1.1 / WD repeat-containing protein 5 / Histone H4 / Ubiquitin-40S ribosomal protein S27a / Retinoblastoma-binding protein 5 / Histone H2A / Histone-lysine N-methyltransferase 2C / Set1/Ash2 histone methyltransferase complex subunit ASH2
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.
Validation Report
SummaryFull reportAbout validation report
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

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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
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein/peptide , 9 types, 13 molecules AEBFCGDHKNORT

#1: Protein/peptide 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
#2: Protein/peptide 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/peptide 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
#4: Protein/peptide 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/peptide Histone-lysine N-methyltransferase 2C / 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/peptide 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/peptide 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/peptide 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/peptide 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 / Zinc

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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

Type: COMPLEX

IDNameEntity IDParent-IDSource
1Human MLL3 complex associated with an H2B-monoubiquitinated nucleosome (4.0 angstrom)1,2,3,4,5,6,7,8,9,10,110MULTIPLE SOURCES
2Human MLL3KMT2C1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 111RECOMBINANT
3H2B-monoubiquitinated nucleosome1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 111MULTIPLE SOURCES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Xenopus laevis (African clawed frog)8355
Source (recombinant)

Ncbi tax-ID: 562 / Organism: Escherichia coli (E. coli)

IDEntity assembly-ID
12
23
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 FIELDBright-field microscopy
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

Refinement-ID: ELECTRON MICROSCOPY

TypeDev idealNumber
f_bond_d0.005921207
f_angle_d0.864229905
f_chiral_restr0.05143371
f_plane_restr0.00682785
f_dihedral_angle_d19.043511726

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