OpenCell: Endogenous tagging for the cartography of human cellular organization

Science, Journal Year: 2022, Volume and Issue: 375(6585)

Published: March 10, 2022

Elucidating the wiring diagram of human cell is a central goal postgenomic era. We combined genome engineering, confocal live-cell imaging, mass spectrometry, and data science to systematically map localization interactions proteins. Our approach provides data-driven description molecular spatial networks that organize proteome. Unsupervised clustering these delineates functional communities facilitate biological discovery. found remarkably precise information can be derived from protein patterns, which often contain enough identify interactions, RNA binding proteins form specific subgroup defined by unique interaction properties. Paired with fully interactive website (opencell.czbiohub.org), our work constitutes resource for quantitative cartography cellular organization.

Language: Английский

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The molecular basis for cellular function of intrinsically disordered protein regions

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 187 - 211

Published: Nov. 13, 2023

Language: Английский

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Functional partitioning of transcriptional regulators by patterned charge blocks

Cell, Journal Year: 2023, Volume and Issue: 186(2), P. 327 - 345.e28

Published: Jan. 1, 2023

Language: Английский

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Transcription factors interact with RNA to regulate genes

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(14), P. 2449 - 2463.e13

Published: July 1, 2023

Language: Английский

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Plant transcription factors — being in the right place with the right company

Current Opinion in Plant Biology, Journal Year: 2021, Volume and Issue: 65, P. 102136 - 102136

Published: Nov. 29, 2021

Language: Английский

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Systematic identification of conditionally folded intrinsically disordered regions by AlphaFold2

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(44)

Published: Oct. 25, 2023

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 fivefold 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

Language: Английский

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Direct prediction of intrinsically disordered protein conformational properties from sequence

Nature Methods, Journal Year: 2024, Volume and Issue: 21(3), P. 465 - 476

Published: Jan. 31, 2024

Abstract Intrinsically disordered regions (IDRs) are ubiquitous across all domains of life and play a range functional roles. While folded generally well described by stable three-dimensional structure, IDRs exist in collection interconverting states known as an ensemble. This structural heterogeneity means that largely absent from the Protein Data Bank, contributing to lack computational approaches predict ensemble conformational properties sequence. Here we combine rational sequence design, large-scale molecular simulations deep learning develop ALBATROSS, deep-learning model for predicting dimensions IDRs, including radius gyration, end-to-end distance, polymer-scaling exponent asphericity, directly sequences at proteome-wide scale. ALBATROSS is lightweight, easy use accessible both locally installable software package point-and-click-style interface via Google Colab notebooks. We first demonstrate applicability our predictors examining generalizability sequence–ensemble relationships IDRs. Then, leverage high-throughput nature characterize sequence-specific biophysical behavior within between proteomes.

Language: Английский

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Rapid prediction and analysis of protein intrinsic disorder

Protein Science, Journal Year: 2022, Volume and Issue: 31(12)

Published: Nov. 5, 2022

Protein intrinsic disorder is found in all kingdoms of life and known to underpin numerous physiological pathological processes. Computational methods play an important role characterizing identifying intrinsically disordered proteins protein regions. Herein, we present a new high-efficiency web-based predictor named Rapid Intrinsic Disorder Analysis Online (RIDAO) that designed facilitate the application analysis genome-scale structural bioinformatics comparative genomics/proteomics. RIDAO integrates six established predictors into single, unified platform reproduces results individual with near-perfect fidelity. To demonstrate potential applications, construct test set containing more than one million sequences from hundred organisms comprising over 420 residues. Using this set, compare efficiency accessibility (i.e., ease use) five well-known popular predictors, namely: AUCpreD, IUPred3, metapredict V2, flDPnn, SPOT-Disorder2. We show yields per-residue predictions at rate two orders magnitude greater other completely processes under hour. can be accessed free charge https://ridao.app.

Language: Английский

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Aberrant phase separation and nucleolar dysfunction in rare genetic diseases

Nature, Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 8, 2023

Abstract Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact most is unknown as they occur within intrinsically disordered protein regions that poorly defined functions 1–3 . Intrinsically can mediate phase separation and formation biomolecular condensates, such nucleolus 4,5 This suggests mutations proteins may alter condensate properties function 6–8 Here we show a subset disease-associated separation, cause mispartitioning into disrupt nucleolar function. We discover de novo frameshift HMGB1 brachyphalangy, polydactyly tibial aplasia syndrome, rare complex malformation syndrome. The frameshifts replace acidic tail with an arginine-rich basic tail. mutant alters enhances its partitioning causes dysfunction. built catalogue more than 200,000 carboxy-terminal tails identified 600 create transcription factors other proteins. For 12 out 13 tested, mutation enhanced nucleolus, several altered rRNA biogenesis. These data identify syndrome suggest large number dysregulate nucleoli condensates humans.

Language: Английский

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The temperature sensor TWA1 is required for thermotolerance in Arabidopsis

Nature, Journal Year: 2024, Volume and Issue: 629(8014), P. 1126 - 1132

Published: May 15, 2024

Plants exposed to incidences of excessive temperatures activate heat-stress responses cope with the physiological challenge and stimulate long-term acclimation

Language: Английский

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