Conformational ensembles of the human intrinsically disordered proteome

Nature, Год журнала: 2024, Номер 626(8000), С. 897 - 904

Опубликована: Янв. 31, 2024

Язык: Английский

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Direct prediction of intrinsically disordered protein conformational properties from sequence

Nature Methods, Год журнала: 2024, Номер 21(3), С. 465 - 476

Опубликована: Янв. 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.

Язык: Английский

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The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 8, 2024

Abstract Chemokine heterodimers activate or dampen their cognate receptors during inflammation. The CXCL12 chemokine forms with the fully reduced (fr) alarmin HMGB1 a physiologically relevant heterocomplex (frHMGB1•CXCL12) that synergically promotes inflammatory response elicited by G-protein coupled receptor CXCR4. molecular details of complex formation were still elusive. Here we show an integrated structural approach frHMGB1•CXCL12 is fuzzy heterocomplex. Unlike previous assumptions, frHMGB1 and form dynamic equimolar assembly, structured unstructured regions recognizing dimerization surface. We uncover unexpected role acidic intrinsically disordered region (IDR) in its binding to CXCR4 on cell Our work shows interaction diverges from classical rigid heterophilic chemokines dimerization. Simultaneous interference multiple interactions within might offer pharmacological strategies against conditions.

Язык: Английский

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DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 16, 2024

Abstract More than 1600 human transcription factors orchestrate the transcriptional machinery to control gene expression and cell fate. Their function is conveyed through intrinsically disordered regions (IDRs) containing activation or repression domains but lacking quantitative structural ensemble models prevents their mechanistic decoding. Here we integrate single-molecule FRET NMR spectroscopy with molecular simulations showing that DNA binding can lead complex changes in IDR accessibility. The C-terminal of pioneer factor Sox2 highly its conformational dynamics are guided by weak dynamic charge interactions folded domain. Both nucleosome induce major rearrangements without affecting affinity. Remarkably, interdomain redistributed leading variable exposure two critical for transcription. Charged intramolecular allowing redistributions may be common necessary sensitive tuning ensembles.

Язык: Английский

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Enhanced Protein-Protein Interaction Discovery via AlphaFold-Multimer

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 21, 2024

Abstract Accurately mapping protein-protein interactions (PPIs) is critical for elucidating cellular functions and has significant implications health disease. Conventional experimental approaches, while foundational, often fall short in capturing direct, dynamic interactions, especially those with transient or small interfaces. Our study leverages AlphaFold-Multimer (AFM) to re-evaluate high-confidence PPI datasets from Drosophila human. analysis uncovers a limitation of the AFM-derived interface pTM (ipTM) metric, which, reflective structural integrity, can miss physiologically relevant at interfaces within flexible regions. To bridge this gap, we introduce Local Interaction Score (LIS), derived AFM’s Predicted Aligned Error (PAE), focusing on areas low PAE values, indicative high confidence interaction predictions. The LIS method demonstrates enhanced sensitivity detecting PPIs, particularly among that involve By applying large-scale datasets, enhance detection direct interactions. Moreover, present FlyPredictome, an online platform integrates our AFM-based predictions additional information such as gene expression correlations subcellular localization This not only improves upon utility prediction but also highlights potential computational methods complement approaches identification networks.

Язык: Английский

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Prediction of phase separation propensities of disordered proteins from sequence

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 3, 2024

Abstract Phase separation is thought to be one possible mechanism governing the selective cellular enrichment of biomolecular constituents for processes such as transcriptional activation, mRNA regulation, and immune signaling. mediated by multivalent interactions biological macromolecules including intrinsically disordered proteins regions (IDRs). Despite considerable advances in experiments, theory simulations, prediction thermodynamics IDR phase behaviour remains challenging. We combined coarse-grained molecular dynamics simulations active learning develop a fast accurate machine model predict free energy saturation concentration directly from sequence. validate using both experimental computational data. apply our all 27,663 IDRs chain length up 800 residues human proteome find that 1,420 these (5%) are predicted undergo homotypic with transfer energies < −2 k B T . use understand relationship between single-chain compaction separation, changes charge-to hydrophobicity-mediated can break symmetry intra-and inter-molecular interactions. also analyse structural preferences at condensate interfaces substantial heterogeneity determined same sequence properties separation. Our work refines established rules relationships features propensities, models will useful interpreting designing experiments on role design specific propensities.

Язык: Английский

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Protein codes promote selective subcellular compartmentalization

Science, Год журнала: 2025, Номер unknown

Опубликована: Фев. 6, 2025

Cells have evolved mechanisms to distribute ~10 billion protein molecules subcellular compartments where diverse proteins involved in shared functions must assemble. Here, we demonstrate that with share amino acid sequence codes guide them compartment destinations. A language model, ProtGPS, was developed predicts high performance the localization of human excluded from training set. ProtGPS successfully guided generation novel sequences selectively assemble nucleolus. identified pathological mutations change this code and lead altered proteins. Our results indicate contain not only a folding code, but also previously unrecognized governing their distribution compartments.

Язык: Английский

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Molecular determinants of condensate composition

Molecular Cell, Год журнала: 2025, Номер 85(2), С. 290 - 308

Опубликована: Янв. 1, 2025

Язык: Английский

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Emerging regulatory mechanisms and functions of biomolecular condensates: implications for therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Янв. 6, 2025

Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed condensation proteins, nucleic acids, other molecules-in driving efficient dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression intracellular signal transduction, enabling rapid finely tuned responses. Their ability regulate signaling pathways is particularly significant, it requires a careful balance between flexibility precision. Disruption this can lead pathological conditions, including neurodegenerative diseases, cancer, viral infections. Consequently, emerged promising therapeutic targets, with potential offer novel approaches disease treatment. In review, we present recent insights into regulatory mechanisms by which influence pathways, roles health disease, strategies for modulating condensate dynamics approach. Understanding these emerging principles may provide valuable directions developing effective treatments targeting aberrant behavior diseases.

Язык: Английский

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

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 168953 - 168953

Опубликована: Янв. 1, 2025

Язык: Английский

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