Fuzzy protein theory for disordered proteins

Fuxreiter, Mónika

doi:10.1042/bst20200239

Cited by 24 publications

(19 citation statements)

References 63 publications

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“…For the (GSK) n -GFP x systems, we found that tail length and the size/charge of an adjoining patch can provide complementary properties that influence conformational behavior. As a more general model, interactions between polyelectrolytic tails and electrostatically complementary adjoining patches are dictated by a complex balance between energetically favorable IDR-FD interactions vs. unfavorable IDR-IDR interactions, and the conformational entropic cost of interacting with a specific region on the surface ( i.e., the entropic cost of “fuzzy” binding) ( Tompa and Fuxreiter, 2008 ; Arbesú et al., 2018 ; Fuxreiter, 2020 ). An additional feature not well captured in our work is the energetically (entropically) favorable contribution of ion release that conventionally is considered to drive complex coacervation ( Sing and Perry, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Folded domain charge properties influence the conformational behavior of disordered tails

Taneja

Holehouse

2021

Current Research in Structural Biology

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Intrinsically disordered proteins and protein regions (IDRs) make up around 30% of the human proteome where they play essential roles in dictating and regulating many core biological processes. While IDRs are often studied as isolated domains, in naturally occurring proteins most IDRs are found adjacent to folded domains, where they exist as either N- or C-terminal tails or as linkers connecting two folded domains. Prior work has shown that charge properties of IDRs can influence their conformational behavior, both in isolation and in the context of folded domains. In contrast, the converse scenario is less well-explored: how do the charge properties of folded domains influence IDR conformational behavior? To answer this question, we combined a large-scale structural bioinformatics analysis with all-atom implicit solvent simulations of both rationally designed and naturally occurring proteins. Our results reveal three key takeaways. Firstly, the relative position and accessibility of charged residues across the surface of a folded domain can dictate IDR conformational behavior, overriding expectations based on net surface charge properties. Secondly, naturally occurring proteins possess multiple charge patches that are physically accessible to local IDRs. Finally, even modest changes in the local electrostatic environment of a folded domain can substantially modulate IDR-folded domain interactions. Taken together, our results suggest that folded domain surfaces can act as local determinants of IDR conformational behavior.

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Section: Discussionmentioning

confidence: 99%

Folded domain charge properties influence the conformational behavior of disordered tails

Taneja

Holehouse

2021

Current Research in Structural Biology

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“…Thus, protein regions that drive aggregation within liquid-like condensates are capable of switching between disordered and ordered interactions ( 23 ). This interaction property, which changes between interaction modes, is denoted as context-dependence, which leads to a wide variety of cellular behaviors under different conditions ( 35 , 36 ).…”

Section: Principles To Enable the Prediction Of The Condensed State B...mentioning

confidence: 99%

FuzDrop on AlphaFold: visualizing the sequence-dependent propensity of liquid–liquid phase separation and aggregation of proteins

Hatos

Tosatto

Vendruscolo

et al. 2022

Nucleic Acids Research

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Many proteins perform their functions within membraneless organelles, where they form a liquid-like condensed state, also known as droplet state. The FuzDrop method predicts the probability of spontaneous liquid–liquid phase separation of proteins and provides a sequence-based score to identify the regions that promote this process. Furthermore, the FuzDrop method estimates the propensity of conversion of proteins to the amyloid state, and identifies aggregation hot-spots, which can drive the irreversible maturation of the liquid-like droplet state. These predictions can also identify mutations that can induce formation of amyloid aggregates, including those implicated in human diseases. To facilitate the interpretation of the predictions, the droplet-promoting and aggregation-promoting regions can be visualized on protein structures generated by AlphaFold. The FuzDrop server (https://fuzdrop.bio.unipd.it) thus offers insights into the complex behavior of proteins in their condensed states and facilitates the understanding of the functional relationships of proteins.

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“…Especially in situations in which proteins or protein complexes are required to respond to changing cellular conditions by scanning large ensembles of different RNA molecules ( 56 ). As such, our finding represents a logical extension of the fuzzy protein theory for disordered proteins ( 69 , 70 ) by merging the fuzziness and frustration concepts in the energy landscape of proteins with that of RNA molecules ( 71 ). As much as frustration in fuzzy protein/protein complexes causes a multiplicity of specific interactions ( 72 , 73 ), it is conceivable that frustration in RNA/protein complexes is responsible for the observed nonbinary pre-mRNA-binding characteristics of the T. brucei editosome.…”

Section: Discussionmentioning

confidence: 79%

Fuzzy RNA recognition by theTrypanosoma bruceieditosome

Göringer

2022

Nucleic Acids Research

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The assembly of high molecular mass ribonucleoprotein complexes typically relies on the binary interaction of defined RNA sequences or precisely folded RNA motifs with dedicated RNA-binding domains on the protein side. Here we describe a new molecular recognition principle of RNA molecules by a high molecular mass protein complex. By chemically probing the solvent accessibility of mitochondrial pre-mRNAs when bound to the Trypanosoma brucei editosome, we identified multiple similar but non-identical RNA motifs as editosome contact sites. However, by treating the different motifs as mathematical graph objects we demonstrate that they fit a consensus 2D-graph consisting of 4 vertices (V) and 3 edges (E) with a Laplacian eigenvalue of 0.5477 (λ2). We establish that synthetic 4V(3E)-RNAs are sufficient to compete for the editosomal pre-mRNA binding site and that they inhibit RNA editing in vitro. Furthermore, we demonstrate that only two topological indices are necessary to predict the binding of any RNA motif to the editosome with a high level of confidence. Our analysis corroborates that the editosome has adapted to the structural multiplicity of the mitochondrial mRNA folding space by recognizing a fuzzy continuum of RNA folds that fit a consensus graph descriptor.

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Fuzzy protein theory for disordered proteins

Cited by 24 publications

References 63 publications

Folded domain charge properties influence the conformational behavior of disordered tails

Folded domain charge properties influence the conformational behavior of disordered tails

FuzDrop on AlphaFold: visualizing the sequence-dependent propensity of liquid–liquid phase separation and aggregation of proteins

Fuzzy RNA recognition by theTrypanosoma bruceieditosome

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