Disordered regions of condensate-promoting proteins have distinct molecular signatures associated with cellular function

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 168953 - 168953

Published: Jan. 1, 2025

Language: Английский

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PUNCH2: Explore the strategy for intrinsically disordered protein predictor

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(3), P. e0319208 - e0319208

Published: March 26, 2025

Intrinsically disordered proteins (IDPs) and their intrinsically regions (IDRs) lack stable three-dimensional structures, posing significant challenges for computational prediction. This study introduces PUNCH2 PUNCH2-light , advanced predictors designed to address these through curated datasets, innovative feature extraction, optimized neural architectures. By integrating experimental datasets from PDB ( PDB_missing ) fully sequences DisProt DisProt_FD ), we enhanced model performance robustness. Three embedding strategies—One-Hot, MSA-based, PLM-based embeddings—were evaluated, with ProtTrans emerging as the most effective single combined embeddings achieving best results. The employ a 12-layer convolutional network (CNN_L12_narrow), offering balance between accuracy efficiency. combines One-Hot, ProtTrans, MSA-Transformer embeddings, while provides faster alternative excluding MSA-based embeddings. its streamlined variant, are competitive other on CAID2 benchmark rank top two in CAID3 competition. These tools provide efficient, accurate solutions advance IDP research understanding.

Language: Английский

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Clustering of Aromatic Residues in Prion-like Domains Can Tune the Formation, State, and Organization of Biomolecular Condensates

Biochemistry, Journal Year: 2021, Volume and Issue: 60(47), P. 3566 - 3581

Published: Nov. 16, 2021

In immature oocytes, Balbiani bodies are conserved membraneless condensates implicated in oocyte polarization, the organization of mitochondria, and long-term organelle RNA storage. Xenopus laevis, body assembly is mediated by protein Velo1. Velo1 contains an N-terminal prion-like domain (PLD) that essential for formation. PLDs have emerged as a class intrinsically disordered regions can undergo various different types intracellular phase transitions often associated with dynamic, liquid-like condensates. Intriguingly, PLD forms solid-like assemblies. Here we sought to understand why behavior appears be biophysically distinct from other PLD-containing proteins. Through bioinformatic analysis coarse-grained simulations, predict clustering aromatic residues amino acid composition between aromatics influence condensate material properties, organization, driving forces assembly. To test our predictions, redesigned impact targeted sequence changes vivo. We found design evenly spaced shows rapid internal dynamics, probed fluorescent recovery after photobleaching, even when recruited into bodies. Our results suggest might been selected evolution distinctly clustered maintain structure long-lived oocytes. general, work identifies several tunable parameters used augment state, offering road map synthetic

Language: Английский

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Genetic variation associated with condensate dysregulation in disease

Developmental Cell, Journal Year: 2022, Volume and Issue: 57(14), P. 1776 - 1788.e8

Published: July 1, 2022

Language: Английский

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Inducible transcriptional condensates drive 3D genome reorganization in the heat shock response

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(22), P. 4386 - 4399.e7

Published: Nov. 1, 2022

Language: Английский

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Intrinsically disordered regions that drive phase separation form a robustly distinct protein class

Journal of Biological Chemistry, Journal Year: 2022, Volume and Issue: 299(1), P. 102801 - 102801

Published: Dec. 14, 2022

Language: Английский

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Systematic identification of conditionally folded intrinsically disordered regions by AlphaFold2

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Feb. 18, 2022

Abstract The AlphaFold Protein Structure Database contains predicted structures for millions of proteins. For the majority human proteins that contain intrinsically disordered regions (IDRs), which do not adopt a stable structure, it is generally assumed these have low AlphaFold2 confidence scores reflect low-confidence structural predictions. Here, we show assigns confident to nearly 15% IDRs. By comparison experimental NMR data subset IDRs are known conditionally fold (i.e., upon binding or under other specific conditions), find often predicts structure folded state. Based on databases fold, estimate can identify folding at precision as high 88% 10% false positive rate, remarkable considering IDR were minimally represented in its training data. We disease mutations 5-fold enriched over general, and up 80% prokaryotes compared less than 20% eukaryotic These results indicate large proteomes eukaryotes function absence conditional folding, but acquire folds more sensitive mutations. emphasize predictions reveal functionally relevant plasticity within cannot offer realistic ensemble representations Significance Statement machine learning-based methods accurately predict most However, two-thirds segments highly flexible autonomously otherwise (IDRs). In interconvert rapidly between number different conformations, posing significant problem protein prediction define one small conformations. found readily certain conditions (conditional folding). leverage AlphaFold2’s quantify extent across tree life, rationalize disease-causing Classifications : Biological Sciences; Biophysics Computational Biology

Language: Английский

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Deep learning in prediction of intrinsic disorder in proteins

Computational and Structural Biotechnology Journal, Journal Year: 2022, Volume and Issue: 20, P. 1286 - 1294

Published: Jan. 1, 2022

Intrinsic disorder prediction is an active area that has developed over 100 predictors. We identify and investigate a recent trend towards the development of deep neural network (DNN)-based methods. The first DNN-based method was released in 2013 since 2019 learners account for majority new find 13 currently available predictors are diverse their topologies, sizes networks inputs they utilize. empirically show statistically more accurate than other types using blind test dataset from community assessment intrinsic predictions (CAID). also several well-rounded accurate, fast and/or conveniently available. popularity, favorable predictive performance architectural flexibility suggest likely to fuel future disordered Novel hybrid designs could be used adequately accommodate diversity flavors disorder. discuss scarcity methods binding regions need develop this prediction.

Language: Английский

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Metapredict V2: An update to metapredict, a fast, accurate, and easy-to-use predictor of consensus disorder and structure

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: June 9, 2022

ABSTRACT Intrinsically disordered proteins and protein regions make up 20-40% of most eukaryotic proteomes play essential roles in a wide gamut cellular processes, from intracellular trafficking to epigenetic silencing. Given their importance, the ability robustly, quickly, easily identify IDRs within large is critical. Here we present metapredict V2, an update our deep-learning-based disorder predictor metapredict. Metapredict V2 has substantially improved accuracy, more features, user-friendly interface via web server ( https://metapredict.net/ ), Python package, command-line tool. To illustrate V2’s performance undertake systematic analysis human transcription factors, as well that works for synthetic or non-natural proteins. KEY POINTS fast easy-to-use released 2021. was March 2022 includes accuracy new features. now default implementation, although original implementation available ‘legacy’ This manuscript provides summary how compares version (legacy) (V2) will not be submitted journal; if you use please cite paper reference fact being used.

Language: Английский

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CAID prediction portal: a comprehensive service for predicting intrinsic disorder and binding regions in proteins

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(W1), P. W62 - W69

Published: May 29, 2023

Abstract Intrinsic disorder (ID) in proteins is well-established structural biology, with increasing evidence for its involvement essential biological processes. As measuring dynamic ID behavior experimentally on a large scale remains difficult, scores of published predictors have tried to fill this gap. Unfortunately, their heterogeneity makes it difficult compare performance, confounding biologists wanting make an informed choice. To address issue, the Critical Assessment protein Disorder (CAID) benchmarks and binding regions as community blind-test standardized computing environment. Here we present CAID Prediction Portal, web server executing all methods user-defined sequences. The generates output facilitates comparison between methods, producing consensus prediction highlighting high-confidence regions. website contains extensive documentation explaining meaning different statistics providing brief description methods. Predictor visualized interactive feature viewer made available download single table, option recover previous sessions via private dashboard. Portal valuable resource researchers interested studying proteins. at URL: https://caid.idpcentral.org.

Language: Английский

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