TY - JOUR
T1 - Structural plasticity of methyllysine recognition by the tandem Tudor domain of 53BP1
AU - Tong, Qiong
AU - Cui, Gaofeng
AU - Botuyan, Maria Victoria
AU - Rothbart, Scott B.
AU - Hayashi, Ryo
AU - Musselman, Catherine A.
AU - Singh, Namit
AU - Appella, Ettore
AU - Strahl, Brian D.
AU - Mer, Georges
AU - Kutateladze, Tatiana G.
N1 - Funding Information:
This research is supported by grants from the NIH, GM101664 (T.G.K.), CA132878 (G.M.), GM110058 (B.D.S.) and CA181343 (S.B.R.). G.M. acknowledges partial support from the Mayo Clinic SPORE NCI grants P50CA116201 and P50CA108961. This research is also supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH (EA).
Publisher Copyright:
© 2015 Elsevier Ltd.
PY - 2015/2/3
Y1 - 2015/2/3
N2 - 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.
AB - 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.
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U2 - 10.1016/j.str.2014.11.013
DO - 10.1016/j.str.2014.11.013
M3 - Article
C2 - 25579814
AN - SCOPUS:84930189683
SN - 0969-2126
VL - 23
SP - 312
EP - 321
JO - Structure
JF - Structure
IS - 2
ER -