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- PDB-7k6q: Active state Dot1 bound to the H4K16ac nucleosome -

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Basic information

Entry
Database: PDB / ID: 7k6q
TitleActive state Dot1 bound to the H4K16ac nucleosome
Components
  • (DNA (146-MER)) x 2
  • Histone H2A type 1
  • Histone H2B 1.1
  • Histone H3.2
  • Histone H4
  • Histone-lysine N-methyltransferase, H3 lysine-79 specificHistone methyltransferase
  • Ubiquitin
KeywordsStructural Protein/DNA/Transferase / TRANSFERASE / Structural Protein-DNA-Transferase complex
Function / homology
Function and homology information


negative regulation of heterochromatin formation / meiotic recombination checkpoint signaling / : / histone H3K79 trimethyltransferase activity / [histone H3]-lysine79 N-trimethyltransferase / histone H3K79 methyltransferase activity / global genome nucleotide-excision repair / recombinational repair / postreplication repair / mitotic intra-S DNA damage checkpoint signaling ...negative regulation of heterochromatin formation / meiotic recombination checkpoint signaling / : / histone H3K79 trimethyltransferase activity / [histone H3]-lysine79 N-trimethyltransferase / histone H3K79 methyltransferase activity / global genome nucleotide-excision repair / recombinational repair / postreplication repair / mitotic intra-S DNA damage checkpoint signaling / subtelomeric heterochromatin formation / Maturation of protein E / Maturation of protein E / 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 / Membrane binding and targetting of GAG proteins / Constitutive Signaling by NOTCH1 HD Domain Mutants / NOTCH2 Activation and Transmission of Signal to the Nucleus / Endosomal Sorting Complex Required For Transport (ESCRT) / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / Regulation of FZD by ubiquitination / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Negative regulation of FLT3 / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / mitotic G1 DNA damage checkpoint signaling / APC/C:Cdc20 mediated degradation of Cyclin B / p75NTR recruits signalling complexes / Downregulation of ERBB4 signaling / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / PINK1-PRKN Mediated Mitophagy / APC-Cdc20 mediated degradation of Nek2A / TRAF6-mediated induction of TAK1 complex within TLR4 complex / InlA-mediated entry of Listeria monocytogenes into host cells / Pexophagy / Regulation of innate immune responses to cytosolic DNA / VLDLR internalisation and degradation / Downregulation of ERBB2:ERBB3 signaling / NRIF signals cell death from the nucleus / Regulation of BACH1 activity / Activated NOTCH1 Transmits Signal to the Nucleus / Translesion synthesis by REV1 / NF-kB is activated and signals survival / Regulation of PTEN localization / Translesion synthesis by POLK / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / MAP3K8 (TPL2)-dependent MAPK1/3 activation / Translesion synthesis by POLI / Gap-filling DNA repair synthesis and ligation in GG-NER / TICAM1, RIP1-mediated IKK complex recruitment / Downregulation of TGF-beta receptor signaling / Josephin domain DUBs / Activation of IRF3, IRF7 mediated by TBK1, IKBKE / Regulation of activated PAK-2p34 by proteasome mediated degradation / InlB-mediated entry of Listeria monocytogenes into host cell / IKK complex recruitment mediated by RIP1 / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Autodegradation of Cdh1 by Cdh1:APC/C / TNFR1-induced NF-kappa-B signaling pathway / DNA damage checkpoint signaling / APC/C:Cdc20 mediated degradation of Securin / Asymmetric localization of PCP proteins / TCF dependent signaling in response to WNT / SCF-beta-TrCP mediated degradation of Emi1 / Regulation of NF-kappa B signaling / NIK-->noncanonical NF-kB signaling / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / Degradation of DVL / Negative regulators of DDX58/IFIH1 signaling / NOTCH3 Activation and Transmission of Signal to the Nucleus / TNFR2 non-canonical NF-kB pathway / activated TAK1 mediates p38 MAPK activation / Assembly of the pre-replicative complex / Vpu mediated degradation of CD4 / Deactivation of the beta-catenin transactivating complex / Recognition of DNA damage by PCNA-containing replication complex / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Regulation of signaling by CBL / Dectin-1 mediated noncanonical NF-kB signaling / nucleotide-excision repair / Hh mutants are degraded by ERAD / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Fanconi Anemia Pathway / Negative regulation of FGFR3 signaling / Peroxisomal protein import / Degradation of GLI1 by the proteasome / Termination of translesion DNA synthesis / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Degradation of AXIN / Regulation of TNFR1 signaling
Similarity search - Function
Histone H3-K79 methyltransferase, fungi / 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 H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site / Histone H2A signature. ...Histone H3-K79 methyltransferase, fungi / 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 H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site / Histone H2A signature. / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone H2A / Histone 2A / Histone H4, conserved site / Histone H4 signature. / Histone H4 / Histone H4 / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / Histone H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Ubiquitin conserved site / Ubiquitin domain signature. / Ubiquitin domain / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Histone-fold / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
S-ADENOSYLMETHIONINE / DNA / DNA (> 10) / DNA (> 100) / Histone H2B 1.1 / Histone H2A type 1 / Polyubiquitin-C / Histone H4 / Histone H3.2 / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
Saccharomyces cerevisiae (brewer's yeast)
Homo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsValencia-Sanchez, M.I. / De Ioannes, P.E. / Miao, W. / Truong, D.M. / Lee, R. / Armache, J.-P. / Boeke, J.D. / Armache, K.-J.
Funding support United States, 2items
OrganizationGrant numberCountry
David and Lucile Packard Foundationna United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5R01GM115882-03 United States
CitationJournal: Science / Year: 2021
Title: Regulation of the Dot1 histone H3K79 methyltransferase by histone H4K16 acetylation.
Authors: Marco Igor Valencia-Sánchez / Pablo De Ioannes / Miao Wang / David M Truong / Rachel Lee / Jean-Paul Armache / Jef D Boeke / Karim-Jean Armache /
Abstract: Dot1 (disruptor of telomeric silencing-1), the histone H3 lysine 79 (H3K79) methyltransferase, is conserved throughout evolution, and its deregulation is found in human leukemias. Here, we provide ...Dot1 (disruptor of telomeric silencing-1), the histone H3 lysine 79 (H3K79) methyltransferase, is conserved throughout evolution, and its deregulation is found in human leukemias. Here, we provide evidence that acetylation of histone H4 allosterically stimulates yeast Dot1 in a manner distinct from but coordinating with histone H2B ubiquitination (H2BUb). We further demonstrate that this stimulatory effect is specific to acetylation of lysine 16 (H4K16ac), a modification central to chromatin structure. We provide a mechanism of this histone cross-talk and show that H4K16ac and H2BUb play crucial roles in H3K79 di- and trimethylation in vitro and in vivo. These data reveal mechanisms that control H3K79 methylation and demonstrate how H4K16ac, H3K79me, and H2BUb function together to regulate gene transcription and gene silencing to ensure optimal maintenance and propagation of an epigenetic state.
History
DepositionSep 21, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 10, 2021Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
A: Histone H3.2
B: Histone H4
C: Histone H2A type 1
D: Histone H2B 1.1
E: Histone H3.2
F: Histone H4
G: Histone H2A type 1
H: Histone H2B 1.1
I: DNA (146-MER)
J: DNA (146-MER)
K: Histone-lysine N-methyltransferase, H3 lysine-79 specific
L: Ubiquitin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)233,80313
Polymers233,40512
Non-polymers3981
Water0
1


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

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Components

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Protein , 6 types, 10 molecules AEBFCGDHKL

#1: Protein Histone H3.2


Mass: 11562.554 Da / Num. of mol.: 2 / Mutation: K79M, G103A
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
#2: Protein Histone H4 /


Mass: 10403.212 Da / Num. of mol.: 2 / Mutation: K17X
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 type 1


Mass: 11694.650 Da / Num. of mol.: 2 / Mutation: G99R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli) / References: UniProt: P06897
#4: Protein Histone H2B 1.1 / H2B1.1


Mass: 10322.814 Da / Num. of mol.: 2 / Mutation: K120C, S32T
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, H3 lysine-79 specific / Histone methyltransferase / Disrupter of telomere silencing protein 1 / Histone H3-K79 methyltransferase / H3-K79-HMTase / ...Disrupter of telomere silencing protein 1 / Histone H3-K79 methyltransferase / H3-K79-HMTase / Lysine N-methyltransferase 4


Mass: 46686.094 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Production host: Escherichia coli (E. coli)
References: UniProt: Q04089, [histone H3]-lysine79 N-trimethyltransferase
#8: 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: UBC / Production host: Escherichia coli (E. coli) / References: UniProt: P0CG48

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DNA chain , 2 types, 2 molecules IJ

#5: DNA chain DNA (146-MER)


Mass: 44824.570 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: DNA chain DNA (146-MER)


Mass: 45304.863 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 1 types, 1 molecules

#9: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE / S-Adenosyl methionine


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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
IDNameTypeDetailsEntity IDParent-IDSource
1Active state Dot1 bound to the H4K16ac nucleosomeCOMPLEXH4K16 acetylated H2BK120 Ubiquitinated H3K79M#1-#80RECOMBINANT
2HistonesHistoneCOMPLEX#1-#41RECOMBINANT
3Histone-lysine N-methyltransferase, H3 lysine-79 specificHistone methyltransferaseCOMPLEX#71RECOMBINANT
4Polyubiquitin-BCOMPLEX#81RECOMBINANT
5DNA (146-MER)COMPLEX#5-#61RECOMBINANT
Molecular weight
IDEntity assembly-IDExperimental value
11NO
21NO
31NO
41NO
51NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Saccharomyces cerevisiae (brewer's yeast)4932
21Xenopus laevis (African clawed frog)8355
31Homo sapiens (human)9606
41Synthetic construct (others)32630
52Xenopus laevis (African clawed frog)8355
63Saccharomyces cerevisiae (brewer's yeast)4932
74Homo sapiens (human)9606
85Synthetic construct (others)32630
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Escherichia coli (E. coli)562
22Escherichia coli (E. coli)562
33Escherichia coli (E. coli)562
44Escherichia coli (E. coli)562
Buffer solutionpH: 7
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMTrisTris1
250 mMKClKCl1
31 mMMgCl2MgCl21
41 mMDTTDTT1
SpecimenConc.: 0.45 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 297 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 FIELDBright-field microscopy / Nominal magnification: 130000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 10 sec. / Electron dose: 74.5 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1809
EM imaging opticsEnergyfilter slit width: 20 eV
Image scansSampling size: 5 µm

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Processing

EM software
IDNameVersionCategory
2SerialEMimage acquisition
3Leginonimage acquisition
5GctfCTF correction
8UCSF Chimeramodel fitting
9Cootmodel fitting
11PHENIXmodel refinement
12cryoSPARC2.15initial Euler assignment
13cisTEM1final Euler assignment
14cryoSPARC2.15classification
15cisTEM13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 656198
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 292034 / Algorithm: BACK PROJECTION / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
Atomic model building
IDPDB-IDPdb chain-ID 3D fitting-ID
11U2ZA1
23TU41
31UBQA1
45AV5F1

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