DNA-binding protects p53 from interactions with cofactors involved in transcription-independent functions.
Binding-induced conformational changes of a protein at regions distant from the binding site may play crucial roles in protein function and regulation. The p53 tumour suppressor is an example of such an allosterically regulated protein. Little is known, however, about how DNA binding can affect distal sites for transcription factors. Furthermore, the molecular details of how a local perturbation is transmitted through a protein structure are generally elusive and occur on timescales hard to explore by simulations. Thus, we employed state-of-the-art enhanced sampling atomistic simulations to unveil DNA-induced effects on p53 structure and dynamics that modulate the recruitment of cofactors and the impact of phosphorylation at Ser215. We show that DNA interaction promotes a conformational change in a region 3 nm away from the DNA binding site. Specifically, binding to DNA increases the population of an occluded minor state at this distal site by more than 4-fold, whereas phosphorylation traps the protein in its major state. In the minor conformation, the interface of p53 that binds biological partners related to p53 transcription-independent functions is not accessible. Significantly, our study reveals a mechanism of DNA-mediated protection of p53 from interactions with partners involved in the p53 transcription-independent signalling. This also suggests that conformational dynamics is tightly related to p53 signalling.
Computational Biology Laboratory, Unit of Statistics, Bioinformatics and Registry, Strandboulevarden 49, 2100, Copenhagen, Denmark.|Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Matteo
M
Lambrughi
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126, Milan, Italy.
Luca
L
De Gioia
Department of Chemistry and Institute of Structural and Molecular Biology, University College London, London WC1H 0AJ, UK.
Francesco Luigi
FL
Gervasio
Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Kresten
K
Lindorff-Larsen
Cancer and Inflammation Program, Leidos Biomedical Research Inc., Frederick National laboratory, National Cancer Institute, Frederick, MD 21702, USA.|Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Ruth
R
Nussinov
Department of Earth and Environmental Sciences, University of Milano-Bicocca, Piazza della Scienza 1, 20126, Milan, Italy.
Chiara
C
Urani
Department of Earth and Environmental Sciences, University of Milano-Bicocca, Piazza della Scienza 1, 20126, Milan, Italy.
Maurizio
M
Bruschi
Computational Biology Laboratory, Unit of Statistics, Bioinformatics and Registry, Strandboulevarden 49, 2100, Copenhagen, Denmark elenap@cancer.dk.|Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Elena
http://orcid.org/0000-0002-7376-5894
E
Papaleo
D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
D002352:Carrier Proteins; D016159:Tumor Suppressor Protein p53; D004247:DNA