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- PDB-7xct: Cryo-EM structure of Dot1L and H2BK34ub-H3K79Nle nucleosome 2:1 c... -

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Basic information

Entry
Database: PDB / ID: 7xct
TitleCryo-EM structure of Dot1L and H2BK34ub-H3K79Nle nucleosome 2:1 complex
Components
  • (DNA (145-MER)) x 2
  • Histone H2A
  • Histone H2B type 1-K
  • Histone H4
  • Histone domain-containing protein
  • Histone-lysine N-methyltransferase, H3 lysine-79 specific
  • Ubiquitin
KeywordsNUCLEAR PROTEIN / Complex / Dot1L / H2BK34ub / Nucleosome
Function / homology
Function and homology information


[histone H3]-lysine79 N-trimethyltransferase / histone H3K79 methyltransferase activity / histone H3K79 trimethyltransferase activity / regulation of transcription regulatory region DNA binding / hypothalamus gonadotrophin-releasing hormone neuron development / female meiosis I / positive regulation of protein monoubiquitination / regulation of receptor signaling pathway via JAK-STAT / fat pad development / mitochondrion transport along microtubule ...[histone H3]-lysine79 N-trimethyltransferase / histone H3K79 methyltransferase activity / histone H3K79 trimethyltransferase activity / regulation of transcription regulatory region DNA binding / hypothalamus gonadotrophin-releasing hormone neuron development / female meiosis I / positive regulation of protein monoubiquitination / regulation of receptor signaling pathway via JAK-STAT / fat pad development / mitochondrion transport along microtubule / histone H3 methyltransferase activity / histone methyltransferase activity / female gonad development / seminiferous tubule development / male meiosis I / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / subtelomeric heterochromatin formation / energy homeostasis / Replacement of protamines by nucleosomes in the male pronucleus / regulation of neuron apoptotic process / 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 / TICAM1-dependent activation of IRF3/IRF7 / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / 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 / Regulation of pyruvate metabolism / NF-kB is activated and signals survival / Regulation of innate immune responses to cytosolic DNA / Inhibition of DNA recombination at telomere / Downregulation of ERBB2:ERBB3 signaling / Pexophagy / RNA Polymerase I Promoter Opening / NRIF signals cell death from the nucleus / VLDLR internalisation and degradation / Regulation of PTEN localization / Meiotic synapsis / Activated NOTCH1 Transmits Signal to the Nucleus / Assembly of the ORC complex at the origin of replication / Regulation of BACH1 activity / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / MAP3K8 (TPL2)-dependent MAPK1/3 activation / Translesion synthesis by REV1 / TICAM1, RIP1-mediated IKK complex recruitment / DNA damage checkpoint signaling / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / InlB-mediated entry of Listeria monocytogenes into host cell / Translesion synthesis by POLK / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Downregulation of TGF-beta receptor signaling / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / DNA methylation / Josephin domain DUBs / Translesion synthesis by POLI / Regulation of activated PAK-2p34 by proteasome mediated degradation / Condensation of Prophase Chromosomes / Gap-filling DNA repair synthesis and ligation in GG-NER / IKK complex recruitment mediated by RIP1 / positive regulation of protein ubiquitination / Chromatin modifications during the maternal to zygotic transition (MZT) / SIRT1 negatively regulates rRNA expression / HCMV Late Events / PINK1-PRKN Mediated Mitophagy / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / innate immune response in mucosa / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / TNFR1-induced NF-kappa-B signaling pathway
Similarity search - Function
Histone H3-K79 methyltransferase, metazoa / Histone-lysine N-methyltransferase DOT1 domain / Histone H3-K79 methyltransferase / Histone methylation protein DOT1 / Histone-lysine N-methyltransferase DOT1 (EC 2.1.1.43) domain profile. / Histone, subunit A / Histone, subunit A / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / : / Histone H2B signature. ...Histone H3-K79 methyltransferase, metazoa / Histone-lysine N-methyltransferase DOT1 domain / Histone H3-K79 methyltransferase / Histone methylation protein DOT1 / Histone-lysine N-methyltransferase DOT1 (EC 2.1.1.43) domain profile. / Histone, subunit A / Histone, subunit A / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / : / 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 / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Roll / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
S-ADENOSYLMETHIONINE / DNA / DNA (> 10) / DNA (> 100) / Histone H4 / Histone H2B type 1-K / Polyubiquitin-B / Histone H2A / Histone-lysine N-methyltransferase, H3 lysine-79 specific / H3.4 histone
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.72 Å
AuthorsAi, H.S. / Liu, A.J. / Lou, Z.Y. / Liu, L.
Funding support China, 5items
OrganizationGrant numberCountry
Other private2017YFA0505200 China
National Natural Science Foundation of China (NSFC)21977090 China
National Natural Science Foundation of China (NSFC)21532004 China
National Natural Science Foundation of China (NSFC)91753205 China
National Natural Science Foundation of China (NSFC)81621002 China
CitationJournal: Nat Chem Biol / Year: 2022
Title: H2B Lys34 Ubiquitination Induces Nucleosome Distortion to Stimulate Dot1L Activity.
Authors: Huasong Ai / Maoshen Sun / Aijun Liu / Zixian Sun / Tingting Liu / Lin Cao / Lujun Liang / Qian Qu / Zichen Li / Zhiheng Deng / Zebin Tong / Guochao Chu / Xiaolin Tian / Haiteng Deng / Suwen ...Authors: Huasong Ai / Maoshen Sun / Aijun Liu / Zixian Sun / Tingting Liu / Lin Cao / Lujun Liang / Qian Qu / Zichen Li / Zhiheng Deng / Zebin Tong / Guochao Chu / Xiaolin Tian / Haiteng Deng / Suwen Zhao / Jia-Bin Li / Zhiyong Lou / Lei Liu /
Abstract: Ubiquitination-dependent histone crosstalk plays critical roles in chromatin-associated processes and is highly associated with human diseases. Mechanism studies of the crosstalk have been of the ...Ubiquitination-dependent histone crosstalk plays critical roles in chromatin-associated processes and is highly associated with human diseases. Mechanism studies of the crosstalk have been of the central focus. Here our study on the crosstalk between H2BK34ub and Dot1L-catalyzed H3K79me suggests a novel mechanism of ubiquitination-induced nucleosome distortion to stimulate the activity of an enzyme. We determined the cryo-electron microscopy structures of Dot1L-H2BK34ub nucleosome complex and the H2BK34ub nucleosome alone. The structures reveal that H2BK34ub induces an almost identical orientation and binding pattern of Dot1L on nucleosome as H2BK120ub, which positions Dot1L for the productive conformation through direct ubiquitin-enzyme contacts. However, H2BK34-anchored ubiquitin does not directly interact with Dot1L as occurs in the case of H2BK120ub, but rather induces DNA and histone distortion around the modified site. Our findings establish the structural framework for understanding the H2BK34ub-H3K79me trans-crosstalk and highlight the diversity of mechanisms for histone ubiquitination to activate chromatin-modifying enzymes.
History
DepositionMar 25, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 20, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 6, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Sep 7, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Nov 6, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: Ubiquitin
F: Histone H4
G: Histone H2A
H: Histone H2B type 1-K
K: Histone-lysine N-methyltransferase, H3 lysine-79 specific
E: Histone domain-containing protein
A: Histone domain-containing protein
D: Histone H2B type 1-K
C: Histone H2A
B: Histone H4
I: DNA (145-MER)
J: DNA (145-MER)
M: Histone-lysine N-methyltransferase, H3 lysine-79 specific
N: Ubiquitin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)271,31516
Polymers270,51814
Non-polymers7972
Water00
1


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

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Components

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Protein , 6 types, 12 molecules LNFBGCHDKMEA

#1: Protein Ubiquitin


Mass: 8576.831 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P0CG47
#2: Protein Histone H4


Mass: 10193.043 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: A0A3P9NC92
#3: Protein Histone H2A


Mass: 11865.871 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HIST1H2AB, HIST1H2AE, hCG_1640984, hCG_1787383 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q08AJ9
#4: Protein Histone H2B type 1-K / H2B K / HIRA-interacting protein 1


Mass: 10320.800 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: H2BC12, H2BFT, HIRIP1, HIST1H2BK / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O60814
#5: Protein Histone-lysine N-methyltransferase, H3 lysine-79 specific / DOT1-like protein


Mass: 37930.039 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DOT1L / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q8TEK3, histone-lysine N-methyltransferase
#6: Protein Histone domain-containing protein


Mass: 11615.594 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: S4RAZ3

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DNA chain , 2 types, 2 molecules IJ

#7: DNA chain DNA (145-MER)


Mass: 44521.367 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#8: 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, 2 molecules

#9: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H22N6O5S / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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: Complex of Dot1L(1-416) and H2BK34ub 2:1 nucleosome / Type: COMPLEX / Entity ID: #1-#4, #6-#8, #5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.5
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 R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 %

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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 / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingAverage exposure time: 2.56 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 2.72 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 98100 / Symmetry type: POINT

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