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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Macromolecular condensation organizes nucleolar sub-phases to set up a pH gradient

Cell, Journal Year: 2024, Volume and Issue: 187(8), P. 1889 - 1906.e24

Published: March 18, 2024

Nucleoli are multicomponent condensates defined by coexisting sub-phases. We identified distinct intrinsically disordered regions (IDRs), including acidic (D/E) tracts and K-blocks interspersed E-rich regions, as defining features of nucleolar proteins. show that the localization preferences proteins determined their IDRs types RNA or DNA binding domains they encompass. In vitro reconstitutions studies in cells showed how condensation, which combines complex coacervation components, contributes to organization. D/E contribute lowering pH co-condensates formed with RNAs vitro. cells, this sets up a gradient between nucleoli nucleoplasm. By contrast, juxta-nucleolar bodies, have different macromolecular compositions, featuring protein very charge profiles, values equivalent higher than Our findings compositional specificities generate physicochemical properties for condensates.

Language: Английский

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Labile assembly of a tardigrade protein induces biostasis

Protein Science, Journal Year: 2024, Volume and Issue: 33(4)

Published: March 19, 2024

Tardigrades are microscopic animals that survive desiccation by inducing biostasis. To drying tardigrades rely on intrinsically disordered CAHS proteins, which also function to prevent perturbations induced in vitro and heterologous systems. proteins have been shown form gels both vivo, has speculated be linked their protective capacity. However, the sequence features mechanisms underlying gel formation necessity of gelation for protection not demonstrated. Here we report a mechanism fibrillization D similar intermediate filament assembly. We show vitro, restricts molecular motion, immobilizing protecting labile material from harmful effects drying. In observe forms fibrillar networks during osmotic stress. Fibrillar networking improves survival osmotically shocked cells. two emergent properties associated with fibrillization; (i) prevention cell volume change (ii) reduction metabolic activity shock. find there is no significant correlation between maintenance survival, while reduced metabolism survival. Importantly, D's network reversible rates return control levels after fibers resolved. This work provides insights into how induce biostasis through self-assembly gels.

Language: Английский

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Poly(A)-binding protein is an ataxin-2 chaperone that regulates biomolecular condensates

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(12), P. 2020 - 2034.e6

Published: June 1, 2023

Language: Английский

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Clustering Heterogeneous Conformational Ensembles of Intrinsically Disordered Proteins with t-Distributed Stochastic Neighbor Embedding

Journal of Chemical Theory and Computation, Journal Year: 2023, Volume and Issue: 19(14), P. 4711 - 4727

Published: June 20, 2023

Intrinsically disordered proteins (IDPs) populate a range of conformations that are best described by heterogeneous ensemble. Grouping an IDP ensemble into "structurally similar" clusters for visualization, interpretation, and analysis purposes is much-desired but formidable task, as the conformational space IDPs inherently high-dimensional reduction techniques often result in ambiguous classifications. Here, we employ t-distributed stochastic neighbor embedding (t-SNE) technique to generate homogeneous from full We illustrate utility t-SNE clustering two proteins, Aβ42, α-synuclein, their APO states when bound small molecule ligands. Our results shed light on ordered substates within ensembles provide structural mechanistic insights binding modes confer specificity affinity ligand binding. projections preserve local neighborhood information, interpretable visualizations heterogeneity each ensemble, enable quantification cluster populations relative shifts upon approach provides new framework detailed investigations thermodynamics kinetics will aid rational drug design IDPs.

Language: Английский

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The Analytical Flory Random Coil Is a Simple-to-Use Reference Model for Unfolded and Disordered Proteins

The Journal of Physical Chemistry B, Journal Year: 2023, Volume and Issue: 127(21), P. 4746 - 4760

Published: May 18, 2023

Denatured, unfolded, and intrinsically disordered proteins (collectively referred to here as unfolded proteins) can be described using analytical polymer models. These models capture various polymeric properties fit simulation results or experimental data. However, the model parameters commonly require users' decisions, making them useful for data interpretation but less clearly applicable stand-alone reference Here we use all-atom simulations of polypeptides in conjunction with scaling theory parameterize an that behave ideal chains (ν = 0.50). The model, which call Flory random coil (AFRC), requires only amino acid sequence input provides direct access probability distributions global local conformational order parameters. defines a specific state computational compared normalized. As proof-of-concept, AFRC identify sequence-specific intramolecular interactions proteins. We also contextualize curated set 145 different radii gyration obtained from previously published small-angle X-ray scattering experiments is implemented software package available via Google Colab notebook. In summary, simple-to-use guide intuition aid interpreting results.

Language: Английский

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Nitric oxide-mediated S-nitrosylation of IAA17 protein in intrinsically disordered region represses auxin signaling

Journal of genetics and genomics/Journal of Genetics and Genomics, Journal Year: 2023, Volume and Issue: 50(7), P. 473 - 485

Published: May 15, 2023

The phytohormone auxin plays crucial roles in nearly every aspect of plant growth and development. Auxin signaling is activated through the phytohormone-induced proteasomal degradation Auxin/INDOLE-3-ACETIC ACID (Aux/IAA) family transcriptional repressors. Notably, many auxin-modulated physiological processes are also regulated by nitric oxide (NO) that executes its biological effects predominantly protein S-nitrosylation at specific cysteine residues. However, little known about molecular mechanisms regulating interactive NO networks. Here, we show represses inhibiting IAA17 degradation. induces Cys-70 located intrinsically disordered region IAA17, which inhibits TIR1-IAA17 interaction consequently IAA17. accumulation a higher level attenuates response. Moreover, an IAA17C70W nitrosomimetic mutation renders mutated protein, thereby causing partial resistance to defective lateral root Taken together, these results suggest with TIR1, negatively signaling. This study provides unique insights into redox-based

Language: Английский

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Fine structures of intrinsically disordered proteins

The Journal of Chemical Physics, Journal Year: 2024, Volume and Issue: 160(1)

Published: Jan. 2, 2024

We report simulation studies of 33 single intrinsically disordered proteins (IDPs) using coarse-grained bead-spring models where interactions among different amino acids are introduced through a hydropathy matrix and additional screened Coulomb interaction for the charged acid beads. Our two scales (HPS1, HPS2) [Dignon et al., PLoS Comput. Biol. 14, e1005941 (2018); Tesei al. Proc. Natl. Acad. Sci. U. S. A. 118, e2111696118 (2021)] comparison with existing experimental data indicate an optimal parameter ϵ = 0.1 0.2 kcal/mol HPS1 HPS2 scales. use these best-fit parameters to investigate both universal aspects as well fine structures individual IDPs by introducing characteristics. (i) First, we polymer-specific scaling relations in [Bair J. Chem. Phys. 158, 204902 (2023)] homopolymers. By studying scaled end-to-end distances ⟨RN2⟩/(2Lℓp) transverse fluctuations l̃⊥2=⟨l⊥2⟩/L, demonstrate that broadly characterized Flory exponent ν ≃ 0.56 conclusion conformations interpolate between Gaussian self-avoiding random walk chains. Then, introduce (ii) Wilson charge index (W) captures essential features distribution sequence space (iii) skewness (S) finer shape variation gyration radii distributions function net per residue asymmetry parameter. Finally, our study (iv) ⟨Rg⟩ salt concentration provides another important metric bring out characteristics IDPs, which may carry relevant information origin life.

Language: Английский

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Aberrant phase separation is a common killing strategy of positively charged peptides in biology and human disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 9, 2023

Positively charged repeat peptides are emerging as key players in neurodegenerative diseases. These can perturb diverse cellular pathways but a unifying framework for how such promiscuous toxicity arises has remained elusive. We used mass-spectrometry-based proteomics to define the protein targets of these neurotoxic and found that they all share similar sequence features drive their aberrant condensation with positively peptides. trained machine learning algorithm detect unexpectedly discovered this mode is not limited human expansion disorders evolved countless times across tree life form cationic antimicrobial venom demonstrate an excess positive charge necessary sufficient killer activity, which we name 'polycation poisoning'. findings reveal ancient conserved mechanism inform ways leverage its design rules new generations bioactive

Language: Английский

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Nuclear speckle proteins form intrinsic and MALAT1-dependent microphases

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Nuclear speckles are enriched in serine / arginine rich splicing factors (SRSFs), such as SRSF1. Splicing and proteins TDP-43 concentrate into distinct speckle territories to enable pre-mRNA processing. We have discovered that SRSFs block copolymers the protein-specific interplay of inter-block repulsions attractions drives spontaneous microphase separation. This gives rise size-limited, ordered assemblies, 30 - 45 nm diameter. Depending on protein, each comprises several tens hundreds molecules. The sub-micron scale observed cells shown be clusters microphases. regulatory lncRNA MALAT1 binds preferentially SRSF1 microphases enhance separation alter structures. Microphase enables concentration finite numbers assemblies with nanoscale structures can modulated by . Our findings provide a structural framework for functional organization factors.

Language: Английский

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