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==Solution structure of 53BP1 tandem Tudor domains in complex with a p53K370me2 peptide==
==Solution structure of 53BP1 tandem Tudor domains in complex with a p53K370me2 peptide==
<StructureSection load='2mwo' size='340' side='right' caption='[[2mwo]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
<StructureSection load='2mwo' size='340' side='right'caption='[[2mwo]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[2mwo]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MWO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2MWO FirstGlance]. <br>
<table><tr><td colspan='2'>[[2mwo]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MWO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MWO FirstGlance]. <br>
</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MLY:N-DIMETHYL-LYSINE'>MLY</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MLY:N-DIMETHYL-LYSINE'>MLY</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2mwp|2mwp]]</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=2mwo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mwo OCA], [https://pdbe.org/2mwo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mwo RCSB], [https://www.ebi.ac.uk/pdbsum/2mwo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mwo ProSAT]</span></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=2mwo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mwo OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2mwo RCSB], [http://www.ebi.ac.uk/pdbsum/2mwo PDBsum]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/TP53B_HUMAN TP53B_HUMAN]] Note=A chromosomal aberration involving TP53BP1 is found in a form of myeloproliferative disorder chronic with eosinophilia. Translocation t(5;15)(q33;q22) with PDGFRB creating a TP53BP1-PDGFRB fusion protein. [[http://www.uniprot.org/uniprot/P53_HUMAN P53_HUMAN]] Note=TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma.  Defects in TP53 are a cause of esophageal cancer (ESCR) [MIM:[http://omim.org/entry/133239 133239]].  Defects in TP53 are a cause of Li-Fraumeni syndrome (LFS) [MIM:[http://omim.org/entry/151623 151623]]. LFS is an autosomal dominant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed (PubMed:8118819 and PubMed:8718514) and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers.<ref>PMID:10570149</ref> <ref>PMID:1933902</ref> <ref>PMID:1978757</ref> <ref>PMID:2259385</ref> <ref>PMID:1737852</ref> <ref>PMID:1565144</ref> <ref>PMID:7887414</ref> <ref>PMID:8825920</ref> <ref>PMID:9452042</ref> <ref>PMID:10484981</ref>  Defects in TP53 are involved in head and neck squamous cell carcinomas (HNSCC) [MIM:[http://omim.org/entry/275355 275355]]; also known as squamous cell carcinoma of the head and neck.  Defects in TP53 are a cause of lung cancer (LNCR) [MIM:[http://omim.org/entry/211980 211980]]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.  Defects in TP53 are a cause of choroid plexus papilloma (CPLPA) [MIM:[http://omim.org/entry/260500 260500]]. Choroid plexus papilloma is a slow-growing benign tumor of the choroid plexus that often invades the leptomeninges. In children it is usually in a lateral ventricle but in adults it is more often in the fourth ventricle. Hydrocephalus is common, either from obstruction or from tumor secretion of cerebrospinal fluid. If it undergoes malignant transformation it is called a choroid plexus carcinoma. Primary choroid plexus tumors are rare and usually occur in early childhood.<ref>PMID:12085209</ref>  Defects in TP53 are a cause of adrenocortical carcinoma (ADCC) [MIM:[http://omim.org/entry/202300 202300]]. ADCC is a rare childhood tumor of the adrenal cortex. It occurs with increased frequency in patients with the Beckwith-Wiedemann syndrome and is a component tumor in Li-Fraumeni syndrome.<ref>PMID:11481490</ref>  Defects in TP53 are the cause of susceptibility to basal cell carcinoma 7 (BCC7) [MIM:[http://omim.org/entry/614740 614740]]. A common malignant skin neoplasm that typically appears on hair-bearing skin, most commonly on sun-exposed areas. It is slow growing and rarely metastasizes, but has potentialities for local invasion and destruction. It usually develops as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. Tumor size can vary from a few millimeters to several centimeters in diameter.<ref>PMID:21946351</ref> 
[https://www.uniprot.org/uniprot/TP53B_HUMAN TP53B_HUMAN] Note=A chromosomal aberration involving TP53BP1 is found in a form of myeloproliferative disorder chronic with eosinophilia. Translocation t(5;15)(q33;q22) with PDGFRB creating a TP53BP1-PDGFRB fusion protein.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/TP53B_HUMAN TP53B_HUMAN]] Plays a key role in the response to DNA damage. May have a role in checkpoint signaling during mitosis. Enhances TP53-mediated transcriptional activation.<ref>PMID:12364621</ref> <ref>PMID:17190600</ref> [[http://www.uniprot.org/uniprot/P53_HUMAN P53_HUMAN]] Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; te function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seem to have to effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis.<ref>PMID:9840937</ref> <ref>PMID:11025664</ref> <ref>PMID:12810724</ref> <ref>PMID:15186775</ref> <ref>PMID:15340061</ref> <ref>PMID:17317671</ref> <ref>PMID:17349958</ref> <ref>PMID:19556538</ref> <ref>PMID:20673990</ref> <ref>PMID:20959462</ref> <ref>PMID:22726440</ref> 
[https://www.uniprot.org/uniprot/TP53B_HUMAN TP53B_HUMAN] Plays a key role in the response to DNA damage. May have a role in checkpoint signaling during mitosis. Enhances TP53-mediated transcriptional activation.<ref>PMID:12364621</ref> <ref>PMID:17190600</ref>  
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 2mwo" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Botuyan, M V]]
[[Category: Homo sapiens]]
[[Category: Cui, G]]
[[Category: Large Structures]]
[[Category: Mer, G]]
[[Category: Botuyan MV]]
[[Category: Cell cycle]]
[[Category: Cui G]]
[[Category: Dna damage response]]
[[Category: Mer G]]
[[Category: Transcription-antitumor protein complex]]

Latest revision as of 11:09, 8 March 2023

Solution structure of 53BP1 tandem Tudor domains in complex with a p53K370me2 peptideSolution structure of 53BP1 tandem Tudor domains in complex with a p53K370me2 peptide

Structural highlights

2mwo is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TP53B_HUMAN Note=A chromosomal aberration involving TP53BP1 is found in a form of myeloproliferative disorder chronic with eosinophilia. Translocation t(5;15)(q33;q22) with PDGFRB creating a TP53BP1-PDGFRB fusion protein.

Function

TP53B_HUMAN Plays a key role in the response to DNA damage. May have a role in checkpoint signaling during mitosis. Enhances TP53-mediated transcriptional activation.[1] [2]

Publication Abstract from PubMed

p53 is dynamically regulated through various posttranslational modifications (PTMs), which differentially modulate its function and stability. The dimethylated marks p53K370me2 and p53K382me2 are associated with p53 activation or stabilization and both are recognized by the tandem Tudor domain (TTD) of 53BP1, a p53 cofactor. Here we detail the molecular mechanisms for the recognition of p53K370me2 and p53K382me2 by 53BP1. The solution structures of TTD in complex with the p53K370me2 and p53K382me2 peptides show a remarkable plasticity of 53BP1 in accommodating these diverse dimethyllysine-containing sequences. We demonstrate that dimeric TTDs are capable of interacting with the two PTMs on a single p53K370me2K382me2 peptide, greatly strengthening the 53BP1-p53 interaction. Analysis of binding affinities of TTD toward methylated p53 and histones reveals strong preference of 53BP1 for p53K382me2, H4K20me2, and H3K36me2 and suggests a possible role of multivalent contacts of 53BP1 in p53 targeting to and accumulation at the sites of DNA damage.

Structural Plasticity of Methyllysine Recognition by the Tandem Tudor Domain of 53BP1.,Tong Q, Cui G, Botuyan MV, Rothbart SB, Hayashi R, Musselman CA, Singh N, Appella E, Strahl BD, Mer G, Kutateladze TG Structure. 2015 Jan 8. pii: S0969-2126(14)00406-7. doi:, 10.1016/j.str.2014.11.013. PMID:25579814[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Wang B, Matsuoka S, Carpenter PB, Elledge SJ. 53BP1, a mediator of the DNA damage checkpoint. Science. 2002 Nov 15;298(5597):1435-8. Epub 2002 Oct 3. PMID:12364621 doi:10.1126/science.1076182
  2. ↑ Botuyan MV, Lee J, Ward IM, Kim JE, Thompson JR, Chen J, Mer G. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell. 2006 Dec 29;127(7):1361-73. PMID:17190600 doi:10.1016/j.cell.2006.10.043
  3. ↑ Tong Q, Cui G, Botuyan MV, Rothbart SB, Hayashi R, Musselman CA, Singh N, Appella E, Strahl BD, Mer G, Kutateladze TG. Structural Plasticity of Methyllysine Recognition by the Tandem Tudor Domain of 53BP1. Structure. 2015 Jan 8. pii: S0969-2126(14)00406-7. doi:, 10.1016/j.str.2014.11.013. PMID:25579814 doi:http://dx.doi.org/10.1016/j.str.2014.11.013
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