TY - JOUR
T1 - An acetyl-methyl switch drives a conformational change in p53
AU - Tong, Qiong
AU - Mazur, Sharlyn J.
AU - Rincon-Arano, Hector
AU - Rothbart, Scott B.
AU - Kuznetsov, Dmitry M.
AU - Cui, Gaofeng
AU - Liu, Wallace H.
AU - Gete, Yantenew
AU - Klein, Brianna J.
AU - Jenkins, Lisa
AU - Mer, Georges
AU - Kutateladze, Andrei G.
AU - Strahl, Brian D.
AU - Groudine, Mark
AU - Appella, Ettore
AU - Kutateladze, Tatiana G.
N1 - Funding Information:
We thank Siddhartha Roy and Catherine Musselman for help with experiments and Jay Nix at beamline 4.2.2 of the ALS in Berkeley for help with X-ray crystallographic data collection. We thank the ENCODE Consortium and the ENCODE production laboratories (Ren Lab-LICR-SCSD) that generated data sets used in this study. This research is supported by grants from the NIH, GM101664 (T.G.K.), HL65440 (M.G.), T32CA009657 (H.R-A), GM110058 (B.D.S.), CA181343 (S.B.R.), CA132878 (G.M.), and GM093930 (A.G.K.), and, in part, by the Intramural Research Program of the National Cancer Institute, NIH (E.A.).
Publisher Copyright:
© 2015 Elsevier Ltd.
PY - 2015/2/3
Y1 - 2015/2/3
N2 - Individual 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 Å 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 α-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.
AB - Individual 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 Å 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 α-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.
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U2 - 10.1016/j.str.2014.12.010
DO - 10.1016/j.str.2014.12.010
M3 - Article
C2 - 25651062
AN - SCOPUS:84930189594
SN - 0969-2126
VL - 23
SP - 322
EP - 331
JO - Structure with Folding & design
JF - Structure with Folding & design
IS - 2
ER -