2mwp

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Solution structure of 53BP1 tandem Tudor domains in complex with a p53K382me2 peptide

Structural highlights

2mwp 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.
Method:Solution NMR, 20 models
Ligands:MLY
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.

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Citations
8 reviews cite this structure
Targeting p53 pathways: mechanisms, structures, and advances in therapy.
Wang et al. (2023)
7 more
15 other articles
No citations found

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

Contents


PDB ID 2mwp

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