Multifunctional Intrinsically Disordered Regions in Transcription Factors

Már, Matti; Nitsenko, Kateryna; Heidarsson, Pétur O.

doi:10.1002/chem.202203369

Cited by 30 publications

(27 citation statements)

References 191 publications

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“…On the face of it, the high evolutionary rate of changes in the amino acid sequence in p53TAD, evident from the comparison of different extant tetrapods (Figure S6), is hard to reconcile with its interactions with both MDM2 and CBP/p300, and the centrality of p53 as a pleiotropic hub protein involved in multiple pathways (Levine, 2020). However, recent studies have shown that the exact sequence of TADs are often not crucial for binding coactivators as long as key elements are present in the binding motif, in particular hydrophobic residues (Trp, Leu) separated by negatively charged Asp or Glu (Zarin et al, 2017; Sanborn et al, 2021; Staller et al, 2022; Már et al, 2023). It has also been shown that hub proteins such as p53 that connect different biological “modules” (intermodule hubs) are generally less constrained and evolve faster than hub proteins regulating a specific biological process (intramodule hubs).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…S6), is hard to reconcile with its interactions with both MDM2 and CBP/p300, and the centrality of p53 as a pleiotropic hub protein involved in multiple pathways (56). However, recent studies have shown that the exact sequence of transactivation domains are often not crucial for binding coactivators as long as key elements are present in the binding motif, in particular hydrophobic residues (Trp, Leu) separated by negatively charged Asp or Glu (57)(58)(59)(60). It has also been shown that hub proteins such as p53 that connect different biological "modules" (intermodule hubs) are generally less constrained and evolve faster than hub proteins regulating a specific biological process (intramodule hubs) (61,62).…”

Section: Discussionmentioning

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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“…Acting as hubs in PPI networks, the biological functions of IDPs significantly diverge from those of their ordered counterparts. IDPs are predominantly engaged in signal regulation 15,16 and gene transcription regulation, 17,18 while ordered proteins are primarily involved in catalysis and transport. Transcription factors 17,122 exemplify the role of disordered proteins.…”

Section: Interactions Of Idps With Other Biological Moleculesmentioning

confidence: 99%

“…The dynamic structural characteristics of IDPs present several benefits, 14 including high flexibility, high specificity with low affinity binding, and easy regulation through posttranslational modifications (PTMs). These attributes lay the foundation for their ubiquitous involvement in signal transduction and transcription regulation processes across archaea, bacteria, plant, and animal cells 15–18 …”

Section: Introductionmentioning

confidence: 99%

Rational drug design targeting intrinsically disordered proteins

Wang,

Xiong,

Lai

2023

WIREs Comput Mol Sci

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Intrinsically disordered proteins (IDPs) are proteins that perform important biological functions without well‐defined structures under physiological conditions. IDPs can form fuzzy complexes with other molecules, participate in the formation of membraneless organelles, and function as hubs in protein–protein interaction networks. The malfunction of IDPs causes major human diseases. However, drug design targeting IDPs remains challenging due to their highly dynamic structures and fuzzy interactions. Turning IDPs into druggable targets provides a great opportunity to extend the druggable target‐space for novel drug discovery. Integrative structural biology approaches that combine information derived from computational simulations, artificial intelligence/data‐driven analysis and experimental studies have been used to uncover the dynamic structures and interactions of IDPs. An increasing number of ligands that directly bind IDPs have been found either by target‐based experimental and computational screening or phenotypic screening. Along with the understanding of IDP binding with its partners, structure‐based drug design strategies, especially conformational ensemble‐based computational ligand screening and computer‐aided ligand optimization algorithms, have greatly accelerated the development of IDP ligands. It is inspiring that several IDP‐targeting small‐molecule and peptide drugs have advanced into clinical trials. However, new computational methods need to be further developed for efficiently discovering and optimizing specific and potent ligands for the vast number of IDPs. Along with the understanding of their dynamic structures and interactions, IDPs are expected to become valuable treasure of drug targets.This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics

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Multifunctional Intrinsically Disordered Regions in Transcription Factors

Cited by 30 publications

References 191 publications

Evolution of affinity between p53 transactivation domain 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

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

Rational drug design targeting intrinsically disordered proteins

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