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- EMDB-0652: Structural basis of Dot1L stimulation by histone H2B lysine 120 u... -

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Basic information

Entry
Database: EMDB / ID: EMD-0652
TitleStructural basis of Dot1L stimulation by histone H2B lysine 120 ubiquitination. 3.5A reconstruction of Dot1L on H2BK120Ub nucleosome
Map dataFinal map from cisTEM, filtered at 3.5A, unsharpened
Sample
  • Complex: Cryo-EM structure of human Dot1L bound to H2BK120Ub nucleosome at 3.5A resolution
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 / histone H3 methyltransferase activity ...[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 / histone H3 methyltransferase activity / mitochondrion transport along microtubule / 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 / regulation of neuron apoptotic process / neuron projection morphogenesis / regulation of proteasomal protein catabolic process / 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 / 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 / TICAM1-dependent activation of IRF3/IRF7 / 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 / Downregulation of ERBB2:ERBB3 signaling / Pexophagy / NRIF signals cell death from the nucleus / VLDLR internalisation and degradation / Regulation of PTEN localization / Activated NOTCH1 Transmits Signal to the Nucleus / Regulation of BACH1 activity / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / MAP3K8 (TPL2)-dependent MAPK1/3 activation / DNA damage checkpoint signaling / TICAM1, RIP1-mediated IKK complex recruitment / Translesion synthesis by REV1 / 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 / Josephin domain DUBs / Translesion synthesis by POLI / Regulation of activated PAK-2p34 by proteasome mediated degradation / IKK complex recruitment mediated by RIP1 / Gap-filling DNA repair synthesis and ligation in GG-NER / positive regulation of protein ubiquitination / PINK1-PRKN Mediated Mitophagy / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / TNFR1-induced NF-kappa-B signaling pathway / Autodegradation of Cdh1 by Cdh1:APC/C / regulation of mitochondrial membrane potential / APC/C:Cdc20 mediated degradation of Securin / TCF dependent signaling in response to WNT / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Regulation of NF-kappa B signaling / Asymmetric localization of PCP proteins / Ubiquitin-dependent degradation of Cyclin D / activated TAK1 mediates p38 MAPK activation / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / TNFR2 non-canonical NF-kB pathway / AUF1 (hnRNP D0) binds and destabilizes mRNA / Regulation of signaling by CBL / Vpu mediated degradation of CD4 / Negative regulators of DDX58/IFIH1 signaling / NOTCH3 Activation and Transmission of Signal to the Nucleus / Deactivation of the beta-catenin transactivating complex / Assembly of the pre-replicative complex
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 H2B signature. / Histone H2A conserved site / Histone H2A signature. / Histone H2B ...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 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 / 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
Ubiquitin B / Histone H2B 1.1 / Histone H2A type 1 / Polyubiquitin-B / Histone H4 / Histone H3.2 / Histone H2A / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsValencia-Sanchez MI / De Ioannes P / Wang M / Vasilyev N / Chen R / Nudler E / Armache J-P / Armache K-J
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute5R01GM115882-03 United States
Other privateDavid and Lucile Packard Foundation United States
CitationJournal: Mol Cell / Year: 2019
Title: Structural Basis of Dot1L Stimulation by Histone H2B Lysine 120 Ubiquitination.
Authors: Marco Igor Valencia-Sánchez / Pablo De Ioannes / Miao Wang / Nikita Vasilyev / Ruoyu Chen / Evgeny Nudler / Jean-Paul Armache / Karim-Jean Armache /
Abstract: The essential histone H3 lysine 79 methyltransferase Dot1L regulates transcription and genomic stability and is deregulated in leukemia. The activity of Dot1L is stimulated by mono-ubiquitination of ...The essential histone H3 lysine 79 methyltransferase Dot1L regulates transcription and genomic stability and is deregulated in leukemia. The activity of Dot1L is stimulated by mono-ubiquitination of histone H2B on lysine 120 (H2BK120Ub); however, the detailed mechanism is not understood. We report cryo-EM structures of human Dot1L bound to (1) H2BK120Ub and (2) unmodified nucleosome substrates at 3.5 Å and 4.9 Å, respectively. Comparison of both structures, complemented with biochemical experiments, provides critical insights into the mechanism of Dot1L stimulation by H2BK120Ub. Both structures show Dot1L binding to the same extended surface of the histone octamer. In yeast, this surface is used by silencing proteins involved in heterochromatin formation, explaining the mechanism of their competition with Dot1. These results provide a strong foundation for understanding conserved crosstalk between histone modifications found at actively transcribed genes and offer a general model of how ubiquitin might regulate the activity of chromatin enzymes.
History
DepositionMar 9, 2019-
Header (metadata) releaseApr 24, 2019-
Map releaseApr 24, 2019-
UpdateJun 19, 2019-
Current statusJun 19, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.2
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 1.2
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6o96
  • Surface level: 1.2
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0652.png

Downloads & links

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Map

FileDownload / File: emd_0652.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFinal map from cisTEM, filtered at 3.5A, unsharpened
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 320 pix.
= 331.2 Å		1.04 Å/pix.
x 320 pix.
= 331.2 Å		1.04 Å/pix.
x 320 pix.
= 331.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.035 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.2 / Movie #1: 1.2
Minimum - Maximum-8.897007 - 13.8018
Average (Standard dev.)-0.007490441 (±0.34495002)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 331.19998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0351.0351.035
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z331.200331.200331.200
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-8.89713.802-0.007

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Supplemental data

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Additional map: Final map from cisTEM, filtered at 3.3A, -20 bfactor

Fileemd_0652_additional.map
AnnotationFinal map from cisTEM, filtered at 3.3A, -20 bfactor
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map 1

Fileemd_0652_half_map_1.map
AnnotationHalf-map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map 1

Fileemd_0652_half_map_2.map
AnnotationHalf-map 1
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Cryo-EM structure of human Dot1L bound to H2BK120Ub nucleosome at...

EntireName: Cryo-EM structure of human Dot1L bound to H2BK120Ub nucleosome at 3.5A resolution
Components
  • Complex: Cryo-EM structure of human Dot1L bound to H2BK120Ub nucleosome at 3.5A resolution

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Supramolecule #1: Cryo-EM structure of human Dot1L bound to H2BK120Ub nucleosome at...

SupramoleculeName: Cryo-EM structure of human Dot1L bound to H2BK120Ub nucleosome at 3.5A resolution
type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli) / Recombinant strain: BL21(DE3)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridSupport film - Material: CARBON / Support film - topology: HOLEY / Details: unspecified
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295.15 K / Instrument: FEI VITROBOT MARK I
Details: 3 ul of Dot1L-nucleosome complexes were applied to a glow discharged Quantifoil holey carbon grid (1.2 um hole size, 200 mesh), blotted in a Vitrobot Mark III (FEI Company) using 1.5 seconds ...Details: 3 ul of Dot1L-nucleosome complexes were applied to a glow discharged Quantifoil holey carbon grid (1.2 um hole size, 200 mesh), blotted in a Vitrobot Mark III (FEI Company) using 1.5 seconds blotting at 100% humidity, and then plunge-frozen in liquid ethane cooled by liquid nitrogen..
DetailsThis sample was monodisperse

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Sampling interval: 5.0 µm / Average electron dose: 41.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

DetailsFrames were motion corrected using MotionCor2 with dose-weighting
Particle selectionNumber selected: 1466930
CTF correctionSoftware - Name: Gctf
Startup modelType of model: INSILICO MODEL / In silico model: Generated using cryosparc ab initio run
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 211279
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-6o96:
Dot1L bound to the H2BK120 Ubiquitinated nucleosome

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