The Thermodynamic Basis of the Fuzzy Interaction of an Intrinsically Disordered Protein

Hadži, San; Mernik, Andrej; Podlipnik, Črtomir; Loris, Remy; Lah, Jurij

doi:10.1002/anie.201707853

Cited by 33 publications

(35 citation statements)

References 36 publications

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“…This analysis demonstrates that even after binding, the interaction energetics are far from optimal in the fuzzy regions, in accord with experimental data. 16 Consistent with earlier results for individual cases, 32 we have found that both the disordered and structured regions of complexes are enriched in highly frustrated interactions in the bound complexes of disordered proteins. The interface contacts do decrease the frustration level in the disordered protein once bound as compared to the frustration of the free state, but the interactions often still remain suboptimal and energetic conflicts remain to be resolved ( Figures S3 and S4 ).…”

Section: Discussionsupporting

confidence: 90%

Frustration in Fuzzy Protein Complexes Leads to Interaction Versatility

et al. 2021

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Disordered proteins frequently serve as interaction hubs involving a constrained variety of partners. Complexes with different partners frequently exhibit distinct binding modes, involving regions that remain disordered in the bound state. While the conformational properties of disordered proteins are well-characterized in their free states, less is known about the molecular mechanisms by which specificity can be achieved not with one but with multiple partners. Using the energy landscape theory concept of protein frustration, we demonstrate that complexes of disordered proteins exhibit a high degree of local frustration, especically at the binding interface. These suboptimal interactions lead to the possibility of multiple bound substates, each displaying distinct frustration patterns, which are differently populated in complexes with different partners. These results explain how specificity of disordered proteins can be achieved without a single common bound conformation and how the confliict between different interactions can be used to control the binding to multiple partners.

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Section: Discussionsupporting

confidence: 90%

Frustration in Fuzzy Protein Complexes Leads to Interaction Versatility

et al. 2021

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“…A recent experimental example is the detailed study of the thermodynamics of the fuzzy complex between the C-terminal IDR of antitoxin CcdA, which adopts α helical structure at the time of binding the toxin dimer CcdB (HadŽi et al, 2017 ). The authors perform a series of mutations that affect contacting and non-contacting residues.…”

Section: Fuzzy Complexes and Multivalencymentioning

confidence: 99%

Intramolecular Fuzzy Interactions Involving Intrinsically Disordered Domains

Arbesú

Iruela

Fuentes

et al. 2018

Front. Mol. Biosci.

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Structural disorder is an essential ingredient for function in many proteins and protein complexes. Fuzzy complexes describe the many instances where disorder is maintained as a critical element of protein interactions. In this minireview we discuss how intramolecular fuzzy interactions function in signaling complexes. Focussing on the Src family of kinases, we argue that the intrinsically disordered domains that are unique for each of the family members and display a clear fingerprint of long range interactions in Src, might have critical roles as functional sensor or effectors and mediate allosteric communication via fuzzy interactions.

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“…The critical element of the applied framework is to consider motif-interactions with multiple sites. Experimental and computational studies highlight that ID binding is largely influenced by non-native interactions [70][71][72]. Even in case of templated folding, non-native contacts frustrate the binding free energy landscape [73,74], and enable multiple bound configurations [75].…”

Section: Discussionmentioning

confidence: 99%

Altered dynamics may drift pathological fibrillization in membraneless organelles

Tüű-Szabó

Hoffka²,

Duro

et al. 2019

Preprint

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Protein phase transition can generate non-membrane bound cellular compartments, which can convert from liquid-like to solid-like states. While the molecular driving forces of phase separation have been largely understood, much less is known about the mechanisms of material-state conversion. We apply a recently developed algorithm to describe the weak interaction network of multivalent motifs, and simulate the effect of pathological mutations. We demonstrate that linker dynamics is critical to the material-state of biomolecular condensates. We show that linker flexibility/mobility is a major regulator of the weak, heterogeneous meshwork of multivalent motifs, which promotes phase transition and maintains a liquid-like state. Decreasing linker dynamics increases the propensity of amyloidlike fragments via hampering the motif-exchange and reorganization of the weak interaction network. In contrast, increasing linker mobility may compensate rigidifying mutations, suggesting that the meshwork of weak, variable interactions may provide a rescue mechanism from aggregation. Motif affinity, on the other hand, has a moderate impact on fibrillization.Here we demonstrate that the fuzzy framework provides an efficient approach to handle the intricate organization of membraneless organelles, and could also be applicable to screen for pathological effects of mutations. FG FG FGFS N/Q FG RG N/Q RG N/Q FG FG FGFS FG RG N/Q RG N/Q FG FG FGFS N/Q FG RG N/Q RG FGFS FG FG FG Q/N Q/N

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The Thermodynamic Basis of the Fuzzy Interaction of an Intrinsically Disordered Protein

Cited by 33 publications

References 36 publications

Frustration in Fuzzy Protein Complexes Leads to Interaction Versatility

Frustration in Fuzzy Protein Complexes Leads to Interaction Versatility

Intramolecular Fuzzy Interactions Involving Intrinsically Disordered Domains

Altered dynamics may drift pathological fibrillization in membraneless organelles

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