Molecular dynamics of the full-length p53 monomer

Chillemi, Giovanni; Davidovich, P. B.; D’Abramo, Marco; Mametnabiev, Tazhir; Гарабаджиу, А. В.; Desideri, Alessandro; Melino, Gerry

doi:10.4161/cc.26162

Cited by 29 publications

(31 citation statements)

References 175 publications

(175 reference statements)

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“…Thus, we performed an additional set of p53 DBD(91–289) classical MD simulations to examine whether the inclusion of the N-terminal residues influences the dynamics of the S6-S7 loop. In agreement with previous experimental data (39,50,73), our simulations show that the N-terminal residues can interact with the p53 DBD through a network of hydrogen bonds, including residues in the proximity of the S6-S7 loop (such as Thr211 and Arg213) (Figure 3A). However, we do not expect classical unbiased MD simulations lasting a few hundreds of ns to sample the longer timescale dynamics revealed by the NMR experiments (39), as we also previously observed for another protein (28).…”

Section: Resultssupporting

confidence: 92%

DNA-binding protects p53 from interactions with cofactors involved in transcription-independent functions

Lambrughi¹,

Gioia²,

Gervasio³

et al. 2016

Nucleic Acids Res

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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.

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Section: Resultssupporting

confidence: 92%

DNA-binding protects p53 from interactions with cofactors involved in transcription-independent functions

Lambrughi¹,

Gioia²,

Gervasio³

et al. 2016

Nucleic Acids Res

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“…The members of the p53 family, p53, p63 and p73 have been shown to encompass overlapping target genes, interact with one another [146] and play similar biological roles [147-149]. These include common roles in the protection of the reproductive system [150-152], in development [153-159], aging [160, 161], cell death [162-164], cancer [159, 165-167], redox regulation [161, 168, 169], and metabolism [168, 170, 171].…”

Section: Introductionmentioning

confidence: 99%

Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities

et al. 2014

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The ubiquitin proteasome system (UPS) plays a role in the regulation of most cellular pathways, and its deregulation has been implicated in a wide range of human pathologies that include cancer, neurodegenerative and immunological disorders and viral infections. Targeting the UPS by small molecular regulators thus provides an opportunity for the development of therapeutics for the treatment of several diseases. The proteasome inhibitor Bortezomib was approved for treatment of hematologic malignancies by the FDA in 2003, becoming the first drug targeting the ubiquitin proteasome system in the clinic. Development of drugs targeting specific components of the ubiquitin proteasome system, however, has lagged behind, mainly due to the complexity of the ubiquitination reaction and its outcomes. However, significant advances have been made in recent years in understanding the molecular nature of the ubiquitination system and the vast variety of cellular signals that it produces. Additionally, improvement of screening methods, both in vitro and in silico, have led to the discovery of a number of compounds targeting components of the ubiquitin proteasome system, and some of these have now entered clinical trials. Here, we discuss the current state of drug discovery targeting E3 ligases and the opportunities and challenges that it provides.

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“…15 Much of the research in the quest for E3 inhibitors has been finalized for the p53-HDM2 pathway since p53 is an extremely powerful transcription factor crucial in DNA damage response. [16][17][18][19][20][21] Here, the cellular defense to DNA damage is based on sensors and effectors that activates the cell death pathway, [22][23][24] via p53 [25][26][27][28][29] or its family members. [30][31][32][33][34][35][36][37] Like for our recent Itch inhibitor screening, 14 we believe that in a near future innovative E3 inhibitors will be developed.…”

Section: Introductionmentioning

confidence: 99%

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

et al. 2014

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Both in epithelial development as well as in epithelial cancers, the p53 family member p63 plays a crucial role acting as a master transcriptional regulator. P63 steady state protein levels are regulated by the E3 ubiquitin ligase Itch, via a physical interaction between the PPxY consensus sequence (PY motif) of p63 and one of the 4 WW domains of Itch; this substrate recognition process leads to protein-ubiquitylation and p63 proteasomal degradation. The interaction of the WW domains, a highly compact protein-protein binding module, with the short proline-rich sequences is therefore a crucial regulatory event that may offer innovative potential therapeutic opportunity. Previous molecular studies on the Itch-p63 recognition have been performed in vitro using the Itch-WW2 domain and the peptide interacting fragment of p63 (pep63), which includes the PY motif. Itch-WW2-pep63 interaction is also stabilized in vitro by the conformational constriction of the S-S cyclization in the p63 peptide. The PY motif of p63, as also for other proteins, is characterized by the nearby presence of a (T/S)P motif, which is a potential recognition site of the WW domain of the IV group present in the prolyl-isomerase Pin1. In this study, we demonstrate, by in silico and spectroscopical studies using both the linear pep63 and its cyclic form, that the threonine phosphorylation of the (T/S)PPPxY motif may represent a crucial regulatory event of the Itch-mediated p63 ubiquitylation, increasing the Itch-WW domains-p63 recognition event and stabilizing in vivo the Itch-WW-p63 complex. Moreover, our studies confirm that the subsequently trans/cis proline isomerization of (T/S)P motif by the Pin1 prolyl-isomerase, could modulate the E3-ligase interaction, and that the (T/S) p P trans PPxY motif represent the best conformer for the ItchWW-(T/S)PPPxY motif recognition.

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Molecular dynamics of the full-length p53 monomer

Cited by 29 publications

References 175 publications

DNA-binding protects p53 from interactions with cofactors involved in transcription-independent functions

DNA-binding protects p53 from interactions with cofactors involved in transcription-independent functions

Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

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