Probing Surfaces in Dynamic Protein Interactions

Spreitzer, Emil; Usluer, Sinem; Madl, Tobias

doi:10.1016/j.jmb.2020.02.032

Cited by 18 publications

(12 citation statements)

References 194 publications

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“…Accordingly, this flexible region of FOXO4 may interact with p53 through highly heterogeneous transient contacts commonly observed in complexes of intrinsically disordered proteins, which can remain unfolded in bound states and adopt multiple conformations. 43,44 Another possibility could be that the removal of the N-terminal part of FOXO4 affects the behavior of FH-DBD and thus its interaction with p53 TAD.…”

Section: Discussionmentioning

confidence: 99%

“…However, this FOXO4 region appears to be important for the overall stability of the p53:FOXO4 complex (Figure 2a,b) and for its contacts with p53, as corroborated by chemical cross‐linking (Table S1 and Figure S14a). Accordingly, this flexible region of FOXO4 may interact with p53 through highly heterogeneous transient contacts commonly observed in complexes of intrinsically disordered proteins, which can remain unfolded in bound states and adopt multiple conformations 43,44 . Another possibility could be that the removal of the N‐terminal part of FOXO4 affects the behavior of FH‐DBD and thus its interaction with p53 TAD.…”

Section: Discussionmentioning

confidence: 99%

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FOXO4 interacts with p53 TAD and CRD and inhibits its binding to DNA

et al. 2022

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Transcription factor p53 protects cells against tumorigenesis when subjected to various cellular stresses. Under these conditions, p53 interacts with transcription factor Forkhead box O (FOXO) 4, thereby inducing cellular senescence by upregulating the transcription of senescence-associated protein p21. However, the structural details of this interaction remain unclear. Here, we characterize the interaction between p53 and FOXO4 by NMR, chemical cross-linking, and analytical ultracentrifugation. Our results reveal that the interaction between p53 TAD and the FOXO4 Forkhead domain is essential for the overall stability of the p53:FOXO4 complex. Furthermore, contacts involving the N-terminal segment of FOXO4, the C-terminal negative regulatory domain of p53 and the DNA-binding domains of both proteins stabilize the complex, whose formation blocks p53 binding to DNA but without affecting the DNA-binding properties of FOXO4. Therefore, our structural findings may help to understand the intertwined functions of p53 and FOXO4 in cellular homeostasis, longevity, and stress response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

FOXO4 interacts with p53 TAD and CRD and inhibits its binding to DNA

et al. 2022

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“…Solvent paramagnetic relaxation enhancement (sPRE) experiments, which use NMR with the addition of soluble paramagnetic molecules, will provide quantitative information regarding surface accessibility at atomic resolution. These data can be used to map solvent-exposed regions in protein assemblies and allows the detection of transient interactions in fuzzy complexes [ 78 ]. Similar data can be obtained from limited proteolysis [ 79 ] and H/D exchange [ 80 ] mass spectrometry experiments.…”

Section: Tools For Calculating Ppi Dynamicsmentioning

confidence: 99%

Modeling the Dynamics of Protein–Protein Interfaces, How and Why?

2022

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Protein–protein assemblies act as a key component in numerous cellular processes. Their accurate modeling at the atomic level remains a challenge for structural biology. To address this challenge, several docking and a handful of deep learning methodologies focus on modeling protein–protein interfaces. Although the outcome of these methods has been assessed using static reference structures, more and more data point to the fact that the interaction stability and specificity is encoded in the dynamics of these interfaces. Therefore, this dynamics information must be taken into account when modeling and assessing protein interactions at the atomistic scale. Expanding on this, our review initially focuses on the recent computational strategies aiming at investigating protein–protein interfaces in a dynamic fashion using enhanced sampling, multi-scale modeling, and experimental data integration. Then, we discuss how interface dynamics report on the function of protein assemblies in globular complexes, in fuzzy complexes containing intrinsically disordered proteins, as well as in active complexes, where chemical reactions take place across the protein–protein interface.

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“…Solvent paramagnetic relaxation enhancement (sPRE), which uses NMR with the addition of soluble paramagnetic molecules, will provide quantitative information regarding surface accessibility at atomic resolution. This data can be used to map solvent-exposed regions in protein assemblies and allows the detection of transient interactions in fuzzy complexes [99]. Tsytlonok et al investigated the conformational dynamics of the complex formed by the IDP p27 and Cdk2/cyclin A [100].…”

Section: Integrating Experimental Datamentioning

confidence: 99%

When Order Meets Disorder: Modeling and Function of the Protein Interface in Fuzzy Complexes

Sacquin-Mora

Prévost

2021

Biomolecules

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The degree of proteins structural organization ranges from highly structured, compact folding to intrinsic disorder, where each degree of self-organization corresponds to specific functions: well-organized structural motifs in enzymes offer a proper environment for precisely positioned functional groups to participate in catalytic reactions; at the other end of the self-organization spectrum, intrinsically disordered proteins act as binding hubs via the formation of multiple, transient and often non-specific interactions. This review focusses on cases where structurally organized proteins or domains associate with highly disordered protein chains, leading to the formation of interfaces with varying degrees of fuzziness. We present a review of the computational methods developed to provide us with information on such fuzzy interfaces, and how they integrate experimental information. The discussion focusses on two specific cases, microtubules and homologous recombination nucleoprotein filaments, where a network of intrinsically disordered tails exerts regulatory function in recruiting partner macromolecules, proteins or DNA and tuning the atomic level association. Notably, we show how computational approaches such as molecular dynamics simulations can bring new knowledge to help bridging the gap between experimental analysis, that mostly concerns ensemble properties, and the behavior of individual disordered protein chains that contribute to regulation functions.

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Probing Surfaces in Dynamic Protein Interactions

Cited by 18 publications

References 194 publications

FOXO4 interacts with p53 TAD and CRD and inhibits its binding to DNA

FOXO4 interacts with p53 TAD and CRD and inhibits its binding to DNA

Modeling the Dynamics of Protein–Protein Interfaces, How and Why?

When Order Meets Disorder: Modeling and Function of the Protein Interface in Fuzzy Complexes

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