4x34
From Proteopedia
Crystal structure of the 53BP1 tandem tudor domain in complex with p53K381acK382me2
Structural highlights
DiseaseTP53B_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. FunctionTP53B_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 PubMedIndividual posttranslational modifications (PTMs) of p53 mediate diverse p53-dependent responses; however, much less is known about the combinatorial action of adjacent modifications. Here, we describe crosstalk between the early DNA damage response mark p53K382me2 and the surrounding PTMs that modulate binding of p53 cofactors, including 53BP1 and p300. The 1.8 A resolution crystal structure of the tandem Tudor domain (TTD) of 53BP1 in complex with p53 peptide acetylated at K381 and dimethylated at K382 (p53K381acK382me2) reveals that the dual PTM induces a conformational change in p53. The alpha-helical fold of p53K381acK382me2 positions the side chains of R379, K381ac, and K382me2 to interact with TTD concurrently, reinforcing a modular design of double PTM mimetics. Biochemical and nuclear magnetic resonance analyses show that other surrounding PTMs, including phosphorylation of serine/threonine residues of p53, affect association with TTD. Our findings suggest a novel PTM-driven conformation switch-like mechanism that may regulate p53 interactions with binding partners. An Acetyl-Methyl Switch Drives a Conformational Change in p53.,Tong Q, Mazur SJ, Rincon-Arano H, Rothbart SB, Kuznetsov DM, Cui G, Liu WH, Gete Y, Klein BJ, Jenkins L, Mer G, Kutateladze AG, Strahl BD, Groudine M, Appella E, Kutateladze TG Structure. 2015 Feb 3;23(2):322-31. doi: 10.1016/j.str.2014.12.010. PMID:25651062[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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