Evolutionary history of the p53 family DNA-binding domain: insights from an Alvinella pompejana homolog

Zhang, Qiang; Balourdas, Dimitrios-Ilias; Baron, Bruno; Senitzki, Alon; Haran, Tali E.; Wiman, Klas G.; Soussi, Thierry; Joerger, A.C.

doi:10.1038/s41419-022-04653-8

Cited by 13 publications

(11 citation statements)

References 82 publications

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“…N239 is in the vicinity of the L1/S3 pocket, and substitution to Y increases the hydrophobicity of the water tunnel to the COM, potentially contributing to the lower hydration profile of p53 HM. The gain in stability by replacing residue N239 with an aromatic residue was also observed in p63/p73-like proteins present in extremophile invertebrates, which frequently contain F at this position . Together, our analyses point toward properties that may be related to the observed differences in hydration susceptibility.…”

Section: Discussionsupporting

confidence: 65%

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Water Leakage Pathway Leads to Internal Hydration of the p53 Core Domain

et al. 2022

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The gene encoding the p53 tumor suppressor protein is the most frequently mutated oncogene in cancer patients; yet, generalized strategies for rescuing the function of different p53 mutants remain elusive. This work investigates factors that may contribute to the low inherent stability of the wild-type p53 core domain (p53C) and structurally compromised Y220C mutant. Pressure-induced unfolding of p53C was compared to p63C, the p53 family member with the highest stability, the engineered superstable p53C hexamutant (p53C HM), and lower stability p53C Y220C cancerassociated mutant. The following pressure unfolding values (P50% bar) were obtained: p53C 3346, p53C Y220C 2217, p53C HM 3943, and p63C 4326. Molecular dynamics (MD) simulations revealed that p53C Y220C was most prone to water infiltration, followed by p53C, whereas the interiors of p53C HM and p63C remained comparably dry. A strong correlation (r 2 = 0.92) between P50% and extent of interior hydration was observed. The pathways of individual water molecule entry and exit were mapped and analyzed, revealing a common route preserved across the p53 family involving a previously reported pocket, along with a novel surface cleft, both of which appear to be targetable by small molecules. Potential determinants of propensity to water incursion were assessed, including backbone hydrogen bond protection and combined sequence and structure similarity. Collectively, our results indicate that p53C has an intrinsic susceptibility to water leakage, which is exacerbated in a structural class mutant, suggesting that there may be a common avenue for rescuing p53 function.

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Section: Discussionsupporting

confidence: 65%

“…The gain in stability by replacing residue N239 with an aromatic residue was also observed in p63/p73-like proteins present in extremophile invertebrates, which frequently contain F at this position. 49 Together, our analyses point toward properties that may be related to the observed differences in hydration susceptibility.…”

Section: ■ Resultsmentioning

confidence: 67%

Water Leakage Pathway Leads to Internal Hydration of the p53 Core Domain

et al. 2022

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“…Because of this, mutations leading to p53 malfunction are highly correlated with cancer (2). The central position in cell cycle regulation is consistent with an ancient origin of p53, as evident from the presence of genes encoding p53-like proteins across the animal kingdom (3)(4)(5). In well-studied vertebrate animals p53 is kept at appropriate levels in healthy cells through ubiquitination and subsequent degradation (6).…”

Section: Introductionmentioning

confidence: 70%

“…In this paper we conform to the common naming of “p53” and “MDM2” also for non-vertebrate homologs, although it is not formally correct. In fact, the ancestral p53/p63/p73 protein was likely more similar to extant p63 and p73 than to p53 (5).…”

Section: Introductionmentioning

confidence: 99%

Evolution of affinity between p53 and MDM2 across the animal kingdom demonstrates high plasticity of motif-mediated interactions

Mihalič

Åberg

Farkhondehkish

et al. 2023

Preprint

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The interaction between the transcription factor p53 and the ubiquitin ligase MDM2 results in degradation of p53 and is well studied in relation to cancer biology and drug development. Available sequence data suggest that both p53 and MDM2-family proteins are present across the animal kingdom. However, the interacting regions are missing in some animal groups, and it is not clear whether MDM2 interacts with, and regulates p53 in all species. We used phylogenetic analyses and biophysical measurements to examine the evolution of affinity between the interacting protein regions: a conserved 12-residue intrinsically disordered binding motif in the p53 transactivation domain (TAD) and the folded SWIB domain of MDM2. The affinity varied significantly across the animal kingdom. The p53TAD/MDM2 interaction among jawed vertebrates displayed high affinity, in particular for chicken and human proteins (KD around 0.1 μM). The affinity of the bay mussel p53TAD/MDM2 complex was lower (KD = 15 μM) and those from a placozoan, an arthropod and a jawless vertebrate were very low or non-detectable (KD > 100 μM). Binding experiments with reconstructed ancestral p53TAD/MDM2 variants suggested that a micromolar affinity interaction was present in the ancestral bilaterian animal and was later enhanced in tetrapods while lost in other linages. The different evolutionary trajectories of p53TAD/MDM2 affinity during speciation demonstrate high plasticity of motif-mediated protein-protein interactions and the potential for rapid adaptation of p53 regulation during times of change.

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“…In this paper we conform to the common naming of "p53" and "MDM2" also for non-vertebrate homologs, although it is not formally correct. In fact, the ancestral p53/p63/p73 protein was likely more similar to extant p63 and p73 than to p53 (Zhang et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Evolution of affinity between p53 transactivation domain and MDM2 across the animal kingdom demonstrates high plasticity of motif‐mediated interactions

et al. 2023

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The interaction between the transcription factor p53 and the ubiquitin ligase MDM2 results in the degradation of p53 and is well-studied in cancer biology and drug development. Available sequence data suggest that both p53 and MDM2-family proteins are present across the animal kingdom. However, the interacting regions are missing in some animal groups, and it is not clear whether MDM2 interacts with, and regulates p53 in all species. We used phylogenetic analyses and biophysical measurements to examine the evolution of affinity between the interacting protein regions: a conserved 12-residue intrinsically disordered binding motif in the p53 transactivation domain (TAD) and the folded SWIB domain of MDM2. The affinity varied significantly across the animal kingdom. The p53TAD/MDM2 interaction among jawed vertebrates displayed high affinity, in particular for chicken and human proteins (K D around 0.1 μM). The affinity of the bay mussel p53TAD/ MDM2 complex was lower (K D = 15 μM) and those from a placozoan, an arthropod, and a jawless vertebrate were very low or non-detectable (K D > 100 μM). Binding experiments with reconstructed ancestral p53TAD/ MDM2 variants suggested that a micromolar affinity interaction was present in the ancestral bilaterian animal and was later enhanced in tetrapods while lost in other linages. The different evolutionary trajectories of p53TAD/ MDM2 affinity during speciation demonstrate high plasticity of motifmediated interactions and the potential for rapid adaptation of p53 regulation during times of change. Neutral drift in unconstrained disordered regions may underlie the plasticity and explain the observed low sequence conservation in TADs such as p53TAD.Filip Mihalič and Emma Åberg contributed equally to this study.

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Evolutionary history of the p53 family DNA-binding domain: insights from an Alvinella pompejana homolog

Cited by 13 publications

References 82 publications

Water Leakage Pathway Leads to Internal Hydration of the p53 Core Domain

Water Leakage Pathway Leads to Internal Hydration of the p53 Core Domain

Evolution of affinity between p53 and MDM2 across the animal kingdom demonstrates high plasticity of motif-mediated interactions

Evolution of affinity between p53 transactivation domain and MDM2 across the animal kingdom demonstrates high plasticity of motif‐mediated interactions

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