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| | ==Structural model of 53BP1 bound to a ubiquitylated and methylated nucleosome, at 4.5 A resolution== | | ==Structural model of 53BP1 bound to a ubiquitylated and methylated nucleosome, at 4.5 A resolution== |
| - | <StructureSection load='5kgf' size='340' side='right' caption='[[5kgf]], [[Resolution|resolution]] 4.54Å' scene=''> | + | <SX load='5kgf' size='340' side='right' viewer='molstar' caption='[[5kgf]], [[Resolution|resolution]] 4.54Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5kgf]] is a 14 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KGF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KGF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5kgf]] is a 14 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Xenopus_laevis Xenopus laevis] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KGF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KGF FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=M2L:(2R)-2-AMINO-3-(2-DIMETHYLAMINOETHYLSULFANYL)PROPANOIC+ACID'>M2L</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.54Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5kgf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kgf OCA], [http://pdbe.org/5kgf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kgf RCSB], [http://www.ebi.ac.uk/pdbsum/5kgf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kgf ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=M2L:(2R)-2-AMINO-3-(2-DIMETHYLAMINOETHYLSULFANYL)PROPANOIC+ACID'>M2L</scene></td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5kgf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kgf OCA], [https://pdbe.org/5kgf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kgf RCSB], [https://www.ebi.ac.uk/pdbsum/5kgf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kgf ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/H4_XENLA H4_XENLA]] Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. [[http://www.uniprot.org/uniprot/UBB_HUMAN UBB_HUMAN]] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.<ref>PMID:16543144</ref> <ref>PMID:19754430</ref> [[http://www.uniprot.org/uniprot/H32_XENLA H32_XENLA]] Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. | + | [https://www.uniprot.org/uniprot/H4_XENLA H4_XENLA] Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Histone|Histone]] | + | *[[Histone 3D structures|Histone 3D structures]] |
| - | *[[Ubiquitin|Ubiquitin]] | + | *[[3D structures of ubiquitin|3D structures of ubiquitin]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| - | </StructureSection> | + | </SX> |
| - | [[Category: Benlekbir, S]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Durocher, D]] | + | [[Category: Large Structures]] |
| - | [[Category: Rubinstein, J L]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Sicheri, F]] | + | [[Category: Xenopus laevis]] |
| - | [[Category: Wilson, M D]] | + | [[Category: Benlekbir S]] |
| - | [[Category: Chromatin]] | + | [[Category: Durocher D]] |
| - | [[Category: Dna]] | + | [[Category: Rubinstein JL]] |
| - | [[Category: Structural protein-dna complex]] | + | [[Category: Sicheri F]] |
| | + | [[Category: Wilson MD]] |
| Structural highlights
Function
H4_XENLA Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.
Publication Abstract from PubMed
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 A 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.
The structural basis of modified nucleosome recognition by 53BP1.,Wilson MD, Benlekbir S, Fradet-Turcotte A, Sherker A, Julien JP, McEwan A, Noordermeer SM, Sicheri F, Rubinstein JL, Durocher D Nature. 2016 Aug 4;536(7614):100-3. PMID:27462807[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wilson MD, Benlekbir S, Fradet-Turcotte A, Sherker A, Julien JP, McEwan A, Noordermeer SM, Sicheri F, Rubinstein JL, Durocher D. The structural basis of modified nucleosome recognition by 53BP1. Nature. 2016 Aug 4;536(7614):100-3. PMID:27462807 doi:http://dx.doi.org/10.1038/nature18951
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