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- PDB-6kiv: Cryo-EM structure of human MLL1-ubNCP complex (4.0 angstrom) -

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Entry
Database: PDB / ID: 6kiv
TitleCryo-EM structure of human MLL1-ubNCP complex (4.0 angstrom)
Components
  • (DNA (145-MER)) x 2
  • Histone H2A
  • Histone H2B 1.1
  • Histone H3
  • Histone H4
  • Histone-lysine N-methyltransferase 2A
  • 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


Activation of NF-kappaB in B cells / Translesion Synthesis by POLH / Recognition of DNA damage by PCNA-containing replication complex / Translesion synthesis by REV1 / Regulation of TNFR1 signaling / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / ISG15 antiviral mechanism / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Regulation of PLK1 Activity at G2/M Transition / NOTCH2 Activation and Transmission of Signal to the Nucleus ...Activation of NF-kappaB in B cells / Translesion Synthesis by POLH / Recognition of DNA damage by PCNA-containing replication complex / Translesion synthesis by REV1 / Regulation of TNFR1 signaling / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / ISG15 antiviral mechanism / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Regulation of PLK1 Activity at G2/M Transition / NOTCH2 Activation and Transmission of Signal to the Nucleus / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / FCERI mediated NF-kB activation / Constitutive Signaling by NOTCH1 HD Domain Mutants / Stimuli-sensing channels / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Oncogene Induced Senescence / PKMTs methylate histone lysines / Senescence-Associated Secretory Phenotype (SASP) / Oxidative Stress Induced Senescence / Separation of Sister Chromatids / Selenocysteine synthesis / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Regulation of innate immune responses to cytosolic DNA / HATs acetylate histones / Downregulation of TGF-beta receptor signaling / activated TAK1 mediates p38 MAPK activation / Regulation of FZD by ubiquitination / Degradation of DVL / Degradation of AXIN / Asymmetric localization of PCP proteins / AUF1 (hnRNP D0) binds and destabilizes mRNA / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / TAK1 activates NFkB by phosphorylation and activation of IKKs complex / RMTs methylate histone arginines / Circadian Clock / ABC-family proteins mediated transport / Myoclonic epilepsy of Lafora / Deactivation of the beta-catenin transactivating complex / Autodegradation of the E3 ubiquitin ligase COP1 / Glycogen synthesis / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / Activated NOTCH1 Transmits Signal to the Nucleus / ER-Phagosome pathway / TICAM1, RIP1-mediated IKK complex recruitment / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / APC/C:Cdc20 mediated degradation of Securin / SCF-beta-TrCP mediated degradation of Emi1 / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Cyclin B / DDX58/IFIH1-mediated induction of interferon-alpha/beta / NOD1/2 Signaling Pathway / Membrane binding and targetting of GAG proteins / Budding and maturation of HIV virion / Peptide chain elongation / L13a-mediated translational silencing of Ceruloplasmin expression / Downregulation of ERBB2:ERBB3 signaling / Spry regulation of FGF signaling / Downregulation of ERBB4 signaling / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Assembly Of The HIV Virion / NOTCH1 Intracellular Domain Regulates Transcription / TCF dependent signaling in response to WNT / Regulation of activated PAK-2p34 by proteasome mediated degradation / NF-kB is activated and signals survival / p75NTR recruits signalling complexes / NRIF signals cell death from the nucleus / Downstream TCR signaling / Formation of the beta-catenin:TCF transactivating complex / Degradation of beta-catenin by the destruction complex / APC-Cdc20 mediated degradation of Nek2A / Viral mRNA Translation / SCF(Skp2)-mediated degradation of p27/p21 / EGFR downregulation / Vif-mediated degradation of APOBEC3G / Vpu mediated degradation of CD4 / SRP-dependent cotranslational protein targeting to membrane / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / 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 / GTP hydrolysis and joining of the 60S ribosomal subunit / Ribosomal scanning and start codon recognition / Formation of the ternary complex, and subsequently, the 43S complex / Formation of a pool of free 40S subunits / Translation initiation complex formation / Stabilization of p53 / InlB-mediated entry of Listeria monocytogenes into host cell / G2/M Checkpoints / Cyclin D associated events in G1 / CDK-mediated phosphorylation and removal of Cdc6 / Orc1 removal from chromatin / CDT1 association with the CDC6:ORC:origin complex
Ubiquitin domain profile. / C-terminus of histone H2A / Trp-Asp (WD) repeats signature. / Histone H2B signature. / Histone H3 signature 1. / Ubiquitin domain signature. / Histone H4 signature. / Histone H2A signature. / Centromere kinetochore component CENP-T histone fold / Zinc finger PHD-type signature. ...Ubiquitin domain profile. / C-terminus of histone H2A / Trp-Asp (WD) repeats signature. / Histone H2B signature. / Histone H3 signature 1. / Ubiquitin domain signature. / Histone H4 signature. / Histone H2A signature. / Centromere kinetochore component CENP-T histone fold / Zinc finger PHD-type signature. / F/Y rich C-terminus / F/Y-rich N-terminus / CXXC zinc finger domain / Ribosomal protein S27a / SET domain / PHD-finger / Histone H3 signature 2. / Bromodomain profile. / WD domain, G-beta repeat / FYR domain FYRN motif profile. / Extended PHD (ePHD) domain profile. / FYR domain FYRC motif profile. / Zinc finger CXXC-type profile. / Zinc finger PHD-type profile. / Post-SET domain profile. / Trp-Asp (WD) repeats circular profile. / SET domain profile. / B30.2/SPRY domain profile. / Trp-Asp (WD) repeats profile. / SPRY domain / Ubiquitin family / Concanavalin A-like lectin/glucanase domain superfamily / Histone H4, conserved site / Zinc finger, PHD-finger / WD40 repeat, conserved site / WD40-repeat-containing domain / Methyltransferase, trithorax / WD40/YVTN repeat-like-containing domain superfamily / Zinc finger, RING/FYVE/PHD-type / Ubiquitin domain / Zinc-binding ribosomal protein / Zinc finger, FYVE/PHD-type / Histone-fold / Histone H2A/H2B/H3 / TATA box binding protein associated factor (TAF) / FY-rich, C-terminal / Ubiquitin conserved site / G-protein beta WD-40 repeat / Core histone H2A/H2B/H3/H4 / Retinoblastoma-binding protein 5/Swd1 / KMT2A, PHD domain 2 / KMT2A, PHD domain 1 / KMT2A, ePHD domain / S27a-like superfamily / Histone-lysine N-methyltransferase 2A / WD40-repeat-containing protein Swd3/WDR5 / Histone methyltransferase complex subunit ASH2 / Ubiquitin-like domain superfamily / Bromodomain-like superfamily / WD40-repeat-containing domain superfamily / CENP-T/Histone H4, histone fold / Extended PHD (ePHD) domain / Histone H2A conserved site / Histone H2A, C-terminal domain / SPRY domain / FY-rich, N-terminal / Post-SET domain / Ribosomal protein S27a / Histone H2B / Histone H3/CENP-A / Ubiquitin-like domain / SET domain / Zinc finger, CXXC-type / Histone H2A / Zinc finger, PHD-type / Histone H4 / B30.2/SPRY domain / WD40 repeat / Bromodomain
Histone H3 / Histone H2B 1.1 / WD repeat-containing protein 5 / Histone H4 / Ubiquitin-40S ribosomal protein S27a / Histone-lysine N-methyltransferase 2A / Retinoblastoma-binding protein 5 / Histone H2A / 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 (145-MER)
J: DNA (145-MER)
K: Histone-lysine N-methyltransferase 2A
N: Retinoblastoma-binding protein 5
O: Ubiquitin
T: Set1/Ash2 histone methyltransferase complex subunit ASH2
R: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)387,79317
Polymers387,34315
Non-polymers4502
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein/peptide , 9 types, 13 molecules AEBFCGDHKNOTR

#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 2A / Lysine N-methyltransferase 2A / ALL-1 / CXXC-type zinc finger protein 7 / Myeloid/lymphoid or mixed-lineage leukemia / Myeloid/lymphoid or mixed-lineage leukemia protein 1 / Trithorax-like protein / Zinc finger protein HRX


Mass: 24970.539 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KMT2A, ALL1, CXXC7, HRX, HTRX, MLL, MLL1, TRX1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q03164, 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 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
#11: 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

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DNA chain , 2 types, 2 molecules IJ

#5: DNA chain DNA (145-MER)


Mass: 44521.367 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 , 2 types, 2 molecules

#12: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Mass: 384.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20N6O5S / S-Adenosyl-L-homocysteine
#13: 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 MLL1 complex associated with an H2B-monoubiquitinated nucleosome (4.0 angstrom)1,2,3,4,5,6,7,8,9,10,110MULTIPLE SOURCES
2Human MLL1 complexKMT2A1, 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: 127898 / Symmetry type: POINT
RefinementStereochemistry target values: GeoStd + Monomer Library
Refine LS restraints

Refinement-ID: ELECTRON MICROSCOPY

TypeDev idealNumber
f_bond_d0.007121718
f_angle_d0.883730585
f_chiral_restr0.05263438
f_plane_restr0.00672870
f_dihedral_angle_d18.987912038

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