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- PDB-6w5i: Cryo-EM structure of MLL1 in complex with RbBP5, WDR5, SET1, and ... -

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Basic information

Entry
Database: PDB / ID: 6w5i
TitleCryo-EM structure of MLL1 in complex with RbBP5, WDR5, SET1, and ASH2L bound to the nucleosome (Class01)
Components
  • (DNA (147-MER)) x 2
  • Histone H2A
  • Histone H2B 1.1
  • Histone H3.2
  • Histone H4
  • Histone-lysine N-methyltransferase 2A
  • Retinoblastoma-binding protein 5
  • Set1/Ash2 histone methyltransferase complex subunit ASH2
  • WD repeat-containing protein 5
KeywordsTRANSFERASE/STRUCTURAL PROTEIN/DNA / MLL1-NCP / H3K4 methylation / TRANSFERASE / TRANSFERASE-STRUCTURAL PROTEIN-DNA complex
Function / homology
Function and homology information


negative regulation of DNA methylation-dependent heterochromatin formation / protein-cysteine methyltransferase activity / [histone H3]-lysine4 N-methyltransferase / histone H3K4 monomethyltransferase activity / response to potassium ion / unmethylated CpG binding / histone H3K4 trimethyltransferase activity / Epigenetic regulation of gene expression by MLL3 and MLL4 complexes / MLL3/4 complex / regulation of short-term neuronal synaptic plasticity ...negative regulation of DNA methylation-dependent heterochromatin formation / protein-cysteine methyltransferase activity / [histone H3]-lysine4 N-methyltransferase / histone H3K4 monomethyltransferase activity / response to potassium ion / unmethylated CpG binding / histone H3K4 trimethyltransferase activity / Epigenetic regulation of gene expression by MLL3 and MLL4 complexes / MLL3/4 complex / regulation of short-term neuronal synaptic plasticity / MLL1/2 complex / Set1C/COMPASS complex / ATAC complex / NSL complex / definitive hemopoiesis / histone H3K4 methyltransferase activity / Cardiogenesis / embryonic hemopoiesis / T-helper 2 cell differentiation / exploration behavior / anterior/posterior pattern specification / regulation of tubulin deacetylation / histone methyltransferase complex / Formation of WDR5-containing histone-modifying complexes / minor groove of adenine-thymine-rich DNA binding / regulation of cell division / hemopoiesis / MLL1 complex / regulation of embryonic development / membrane depolarization / histone acetyltransferase complex / negative regulation of fibroblast proliferation / spleen development / cellular response to transforming growth factor beta stimulus / homeostasis of number of cells within a tissue / positive regulation of gluconeogenesis / methylated histone binding / transcription initiation-coupled chromatin remodeling / Transferases; Transferring one-carbon groups; Methyltransferases / post-embryonic development / skeletal system development / gluconeogenesis / Deactivation of the beta-catenin transactivating complex / lysine-acetylated histone binding / circadian regulation of gene expression / Formation of the beta-catenin:TCF transactivating complex / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / euchromatin / visual learning / protein modification process / beta-catenin binding / PKMTs methylate histone lysines / mitotic spindle / RMTs methylate histone arginines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Transcriptional regulation of granulopoiesis / response to estrogen / structural constituent of chromatin / nucleosome / RUNX1 regulates transcription of genes involved in differentiation of HSCs / Neddylation / HATs acetylate histones / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / protein-containing complex assembly / fibroblast proliferation / methylation / histone binding / regulation of cell cycle / transcription cis-regulatory region binding / protein heterodimerization activity / apoptotic process / positive regulation of cell population proliferation / DNA damage response / chromatin binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / nucleolus / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / identical protein binding / nucleus / metal ion binding / cytosol
Similarity search - Function
: / : / Set1/Ash2 histone methyltransferase complex subunit ASH2-like, WH / ASH2, PHD zinc finger / Histone methyltransferase complex subunit ASH2 / Retinoblastoma-binding protein 5/Swd1 / KMT2A, ePHD domain / KMT2A, PHD domain 1 / KMT2A, PHD domain 2 / KMT2A, PHD domain 3 ...: / : / Set1/Ash2 histone methyltransferase complex subunit ASH2-like, WH / ASH2, PHD zinc finger / Histone methyltransferase complex subunit ASH2 / Retinoblastoma-binding protein 5/Swd1 / KMT2A, ePHD domain / KMT2A, PHD domain 1 / KMT2A, PHD domain 2 / KMT2A, PHD domain 3 / Methyltransferase, trithorax / : / 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 / CXXC zinc finger domain / Zinc finger, CXXC-type / Zinc finger CXXC-type profile. / Cysteine-rich motif following a subset of SET domains / Post-SET domain / Post-SET domain profile. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / Extended PHD (ePHD) domain / Extended PHD (ePHD) domain profile. / 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 / PHD-finger / Zinc finger PHD-type signature. / : / Zinc finger PHD-type profile. / 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 H2A / Histone 2A / 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 / Zinc finger, PHD-finger / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / Zinc finger, PHD-type / PHD zinc finger / Histone H3 signature 1. / Zinc finger, FYVE/PHD-type / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Histone-fold / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Concanavalin A-like lectin/glucanase domain superfamily / Zinc finger, RING/FYVE/PHD-type / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
DNA / DNA (> 10) / DNA (> 100) / Histone H2B 1.1 / WD repeat-containing protein 5 / Histone H4 / Histone H3.2 / Histone-lysine N-methyltransferase 2A / Retinoblastoma-binding protein 5 / Histone H2A / Set1/Ash2 histone methyltransferase complex subunit ASH2
Similarity search - Component
Biological speciesHomo sapiens (human)
Xenopus laevis (African clawed frog)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.9 Å
AuthorsPark, S.H. / Lee, Y.T. / Ayoub, A. / Dou, Y. / Cho, U.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Center for Research Resources (NIH/NCRR)DK111465 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA250329 United States
CitationJournal: Nat Commun / Year: 2021
Title: Mechanism for DPY30 and ASH2L intrinsically disordered regions to modulate the MLL/SET1 activity on chromatin.
Authors: Young-Tae Lee / Alex Ayoub / Sang-Ho Park / Liang Sha / Jing Xu / Fengbiao Mao / Wei Zheng / Yang Zhang / Uhn-Soo Cho / Yali Dou /
Abstract: Recent cryo-EM structures show the highly dynamic nature of the MLL1-NCP (nucleosome core particle) interaction. Functional implication and regulation of such dynamics remain unclear. Here we show ...Recent cryo-EM structures show the highly dynamic nature of the MLL1-NCP (nucleosome core particle) interaction. Functional implication and regulation of such dynamics remain unclear. Here we show that DPY30 and the intrinsically disordered regions (IDRs) of ASH2L work together in restricting the rotational dynamics of the MLL1 complex on the NCP. We show that DPY30 binding to ASH2L leads to stabilization and integration of ASH2L IDRs into the MLL1 complex and establishes new ASH2L-NCP contacts. The significance of ASH2L-DPY30 interactions is demonstrated by requirement of both ASH2L IDRs and DPY30 for dramatic increase of processivity and activity of the MLL1 complex. This DPY30 and ASH2L-IDR dependent regulation is NCP-specific and applies to all members of the MLL/SET1 family of enzymes. We further show that DPY30 is causal for de novo establishment of H3K4me3 in ESCs. Our study provides a paradigm of how H3K4me3 is regulated on chromatin and how H3K4me3 heterogeneity can be modulated by ASH2L IDR interacting proteins.
History
DepositionMar 13, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 31, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 12, 2022Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

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Assembly

Deposited unit
A: Retinoblastoma-binding protein 5
B: WD repeat-containing protein 5
C: Histone-lysine N-methyltransferase 2A
D: Set1/Ash2 histone methyltransferase complex subunit ASH2
G: Histone H3.2
H: Histone H4
I: Histone H2A
J: Histone H2B 1.1
K: Histone H3.2
L: Histone H4
M: Histone H2A
N: Histone H2B 1.1
O: DNA (147-MER)
P: DNA (147-MER)


Theoretical massNumber of molelcules
Total (without water)377,91514
Polymers377,91514
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area55720 Å2
ΔGint-391 kcal/mol
Surface area115930 Å2

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Components

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Protein , 8 types, 12 molecules ABCDGKHLIMJN

#1: Protein Retinoblastoma-binding protein 5 / RBBP-5 / Retinoblastoma-binding protein RBQ-3


Mass: 59179.359 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
#2: Protein WD repeat-containing protein 5 / BMP2-induced 3-kb gene protein


Mass: 34390.992 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
#3: Protein Histone-lysine N-methyltransferase 2A / Lysine N-methyltransferase 2A / ALL-1 / CXXC-type zinc finger protein 7 / Myeloid/lymphoid or mixed- ...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: 24141.732 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 H3]-lysine4 N-trimethyltransferase
#4: Protein Set1/Ash2 histone methyltransferase complex subunit ASH2 / ASH2-like protein


Mass: 60244.641 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
#5: Protein Histone H3.2 / Histone H3


Mass: 15435.126 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: P84233
#6: 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
#7: Protein Histone H2A


Mass: 14250.499 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: hist1h2aj, h2ac14, LOC494591, XELAEV_18003602mg / Production host: Escherichia coli (E. coli) / References: UniProt: Q6AZJ8
#8: Protein Histone H2B 1.1 / H2B1.1


Mass: 13524.752 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: P02281

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DNA chain , 2 types, 2 molecules OP

#9: DNA chain DNA (147-MER)


Mass: 45138.770 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#10: DNA chain DNA (147-MER)


Mass: 45610.043 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

Component
IDNameTypeEntity IDParent-IDSource
1MLL1 in complex with RbBP5, WDR5, SET1, and ASH2L bound to the nucleosomeCOMPLEXall0MULTIPLE SOURCES
2Retinoblastoma-binding protein 5, WD repeat-containing protein 5, Histone-lysine N-methyltransferase 2A, Set1/Ash2 histone methyltransferase complex subunit ASH2COMPLEX#1-#41RECOMBINANT
3Histone H3.2, Histone H4, Histone H2A type 1, Histone H2B 1.1COMPLEX#5-#81RECOMBINANT
4DNACOMPLEX#9-#101RECOMBINANT
Molecular weightValue: 0.38 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Xenopus laevis (African clawed frog)8355
34synthetic construct (others)32630
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli (E. coli)562
23Escherichia coli (E. coli)562
34synthetic construct (others)32630
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 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 FIELD
Image recordingElectron dose: 64 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.17.1_3660refinement
PHENIX1.17.1_3660refinement
CTF correctionType: PHASE FLIPPING ONLY
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 6.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 13086 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 355.17 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.005420664
ELECTRON MICROSCOPYf_angle_d0.673829206
ELECTRON MICROSCOPYf_chiral_restr0.0433292
ELECTRON MICROSCOPYf_plane_restr0.00462686
ELECTRON MICROSCOPYf_dihedral_angle_d26.61438101

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