Structural highlights
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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The tumor suppressor p53 and the DNA repair factor 53BP1 (p53 binding protein 1) regulate gene transcription and responses to genotoxic stresses. Upon DNA damage, p53 undergoes dimethylation at Lys382 (p53K382me2), and this posttranslational modification is recognized by 53BP1. The molecular mechanism of nonhistone methyl-lysine mark recognition remains unknown. Here we report a 1. 6-A-resolution crystal structure of the tandem Tudor domain of human 53BP1 bound to a p53K382me2 peptide. In the complex, dimethylated Lys382 is restrained by a set of hydrophobic and cation-pi interactions in a cage formed by four aromatic residues and an aspartate of 53BP1. The signature HKKme2 motif of p53, which defines specificity, is identified through a combination of NMR resonance perturbations, mutagenesis, measurements of binding affinities and docking simulations, and analysis of the crystal structures of 53BP1 bound to p53 peptides containing other dimethyl-lysine marks, p53K370me2 (p53 dimethylated at Lys370) and p53K372me2 (p53 dimethylated at Lys372). Binding of the 53BP1 Tudor domain to p53K382me2 may facilitate p53 accumulation at DNA damage sites and promote DNA repair as suggested by chromatin immunoprecipitation and DNA repair assays. Together, our data detail the molecular mechanism of p53-53BP1 association and provide the basis for deciphering the role of this interaction in the regulation of p53 and 53BP1 functions.
Structural insight into p53 recognition by the 53BP1 tandem Tudor domain.,Roy S, Musselman CA, Kachirskaia I, Hayashi R, Glass KC, Nix JC, Gozani O, Appella E, Kutateladze TG J Mol Biol. 2010 May 14;398(4):489-96. Epub 2010 Mar 20. PMID:20307547[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ Roy S, Musselman CA, Kachirskaia I, Hayashi R, Glass KC, Nix JC, Gozani O, Appella E, Kutateladze TG. Structural insight into p53 recognition by the 53BP1 tandem Tudor domain. J Mol Biol. 2010 May 14;398(4):489-96. Epub 2010 Mar 20. PMID:20307547 doi:10.1016/j.jmb.2010.03.024
