TY - JOUR
T1 - Structural Basis for p53 Lys120-Acetylation-Dependent DNA-Binding Mode
AU - Vainer, Radion
AU - Cohen, Sarit
AU - Shahar, Anat
AU - Zarivach, Raz
AU - Arbely, Eyal
N1 - Funding Information:
The authors wish to thank Professor Sir Alan Fersht for helpful discussions. We thank the EMBL staff Dr. H. Belrhali and Dr. B.A. Manjasetty for providing support on the beamline and EMBL-DBT for providing access to the BM14 beamline at the European Synchrotron Radiation Facility. The research leading to these results has received funding from the European Community's Seventh Framework Program ( FP7/2007-2013 ) under BioStruct-X (grant agreement No. 283570) and from the Concern Foundation (CONquer CanCER Now Award to E.A.).
Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/7/31
Y1 - 2016/7/31
N2 - Normal cellular homeostasis depends on tight regulation of gene expression, which requires the modulation of transcription factors' DNA-binding specificity. That said, the mechanisms that allow transcription factors to distinguish between closely related response elements following different cellular signals are not fully understood. In the tumor suppressor protein p53, acetylation of loop L1 residue Lys120 within the DNA-binding domain has been shown to promote the transcription of proapoptotic genes such as bax. Here, we report the crystal structures of Lys120-acetylated p53 DNA-binding domain in complex with a consensus response element and with the natural BAX response element. Our structural analyses reveal that Lys120 acetylation expands the conformational space of loop L1 in the DNA-bound state. Loop L1 flexibility is known to increase p53's DNA-binding specificity, and Lys120-acetylation-dependent conformational changes in loop L1 enable the formation of sequence-dependent DNA-binding modes for p53. Furthermore, binding to the natural BAX response element is accompanied by global conformational changes, deformation of the DNA helical structure, and formation of an asymmetric tetrameric complex. Based on these findings, we suggest a model for p53's Lys120 acetylation-dependent DNA-binding mode.
AB - Normal cellular homeostasis depends on tight regulation of gene expression, which requires the modulation of transcription factors' DNA-binding specificity. That said, the mechanisms that allow transcription factors to distinguish between closely related response elements following different cellular signals are not fully understood. In the tumor suppressor protein p53, acetylation of loop L1 residue Lys120 within the DNA-binding domain has been shown to promote the transcription of proapoptotic genes such as bax. Here, we report the crystal structures of Lys120-acetylated p53 DNA-binding domain in complex with a consensus response element and with the natural BAX response element. Our structural analyses reveal that Lys120 acetylation expands the conformational space of loop L1 in the DNA-bound state. Loop L1 flexibility is known to increase p53's DNA-binding specificity, and Lys120-acetylation-dependent conformational changes in loop L1 enable the formation of sequence-dependent DNA-binding modes for p53. Furthermore, binding to the natural BAX response element is accompanied by global conformational changes, deformation of the DNA helical structure, and formation of an asymmetric tetrameric complex. Based on these findings, we suggest a model for p53's Lys120 acetylation-dependent DNA-binding mode.
KW - Hoogsteen base pairing
KW - apoptosis
KW - genetic code expansion
KW - lysine acetylation
KW - transcription
UR - http://www.scopus.com/inward/record.url?scp=84978539306&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2016.06.009
DO - 10.1016/j.jmb.2016.06.009
M3 - Article
C2 - 27338200
AN - SCOPUS:84978539306
SN - 0022-2836
VL - 428
SP - 3013
EP - 3025
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 15
ER -