5KGF

Structural model of 53BP1 bound to a ubiquitylated and methylated nucleosome, at 4.5 A resolution


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 4.54 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

The structural basis of modified nucleosome recognition by 53BP1.

Wilson, M.D.Benlekbir, S.Fradet-Turcotte, A.Sherker, A.Julien, J.P.McEwan, A.Noordermeer, S.M.Sicheri, F.Rubinstein, J.L.Durocher, D.

(2016) Nature 536: 100-103

  • DOI: https://doi.org/10.1038/nature18951
  • Primary Citation of Related Structures:  
    5KGF

  • PubMed Abstract: 

    DNA double-strand breaks (DSBs) elicit a histone modification cascade that controls DNA repair. This pathway involves the sequential ubiquitination of histones H1 and H2A by the E3 ubiquitin ligases RNF8 and RNF168, respectively. RNF168 ubiquitinates H2A on lysine 13 and lysine 15 (refs 7, 8) (yielding H2AK13ub and H2AK15ub, respectively), an event that triggers the recruitment of 53BP1 (also known as TP53BP1) to chromatin flanking DSBs. 53BP1 binds specifically to H2AK15ub-containing nucleosomes through a peptide segment termed the ubiquitination-dependent recruitment motif (UDR), which requires the simultaneous engagement of histone H4 lysine 20 dimethylation (H4K20me2) by its tandem Tudor domain. How 53BP1 interacts with these two histone marks in the nucleosomal context, how it recognizes ubiquitin, and how it discriminates between H2AK13ub and H2AK15ub is unknown. Here we present the electron cryomicroscopy (cryo-EM) structure of a dimerized human 53BP1 fragment bound to a H4K20me2-containing and H2AK15ub-containing nucleosome core particle (NCP-ubme) at 4.5 Å resolution. The structure reveals that H4K20me2 and H2AK15ub recognition involves intimate contacts with multiple nucleosomal elements including the acidic patch. Ubiquitin recognition by 53BP1 is unusual and involves the sandwiching of the UDR segment between ubiquitin and the NCP surface. The selectivity for H2AK15ub is imparted by two arginine fingers in the H2A amino-terminal tail, which straddle the nucleosomal DNA and serve to position ubiquitin over the NCP-bound UDR segment. The structure of the complex between NCP-ubme and 53BP1 reveals the basis of 53BP1 recruitment to DSB sites and illuminates how combinations of histone marks and nucleosomal elements cooperate to produce highly specific chromatin responses, such as those elicited following chromosome breaks.


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histone H3.2
A, E
136Xenopus laevisMutation(s): 0 
UniProt
Find proteins for P84233 (Xenopus laevis)
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UniProt GroupP84233
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Histone H4
B, F
103Xenopus laevisMutation(s): 0 
UniProt
Find proteins for P62799 (Xenopus laevis)
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Histone H2A type 1
C, G
130Homo sapiensMutation(s): 3 
Gene Names: HIST1H2AGH2AFPHIST1H2AIH2AFCHIST1H2AKH2AFDHIST1H2ALH2AFIHIST1H2AMH2AFN
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Histone H2B type 1-C/E/F/G/I
D, H
126Homo sapiensMutation(s): 0 
Gene Names: HIST1H2BCH2BFLHIST1H2BEH2BFHHIST1H2BFH2BFGHIST1H2BGH2BFAHIST1H2BIH2BFK
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Entity ID: 7
MoleculeChains Sequence LengthOrganismDetailsImage
Tumor suppressor p53-binding protein 1K [auth L],
N [auth K]
21Homo sapiensMutation(s): 0 
Gene Names: TP53BP1
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GTEx:  ENSG00000067369 
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Entity ID: 8
MoleculeChains Sequence LengthOrganismDetailsImage
UbiquitinL [auth O],
M
76Homo sapiensMutation(s): 0 
Gene Names: UBB
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GTEx:  ENSG00000170315 
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Entity ID: 5
MoleculeChains LengthOrganismImage
DNA (145-MER)145synthetic construct
Sequence Annotations
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Entity ID: 6
MoleculeChains LengthOrganismImage
DNA (145-MER)145synthetic construct
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Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
M2L
Query on M2L
B, F
L-PEPTIDE LINKINGC7 H16 N2 O2 SLYS
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 4.54 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 
EM Software:
TaskSoftware PackageVersion
MODEL REFINEMENTPHENIX1.10.1.2115
RECONSTRUCTIONRELION1.3

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Canadian Institutes of Health Research (CIHR)CanadaFDN143343
Canadian Institutes of Health Research (CIHR)CanadaMOP81294
Canadian Institutes of Health Research (CIHR)CanadaFDN143277

Revision History  (Full details and data files)

  • Version 1.0: 2016-07-27
    Type: Initial release
  • Version 1.1: 2016-08-10
    Changes: Database references
  • Version 1.2: 2016-08-17
    Changes: Database references
  • Version 1.3: 2017-09-13
    Changes: Author supporting evidence, Data collection, Database references
  • Version 1.4: 2018-07-18
    Changes: Data collection
  • Version 1.5: 2020-01-15
    Changes: Author supporting evidence