Rapid prediction and analysis of protein intrinsic disorder

Protein Science, Год журнала: 2022, Номер 31(12)

Опубликована: Ноя. 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.

Язык: Английский

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Moonlighting enzymes: when cellular context defines specificity

Cellular and Molecular Life Sciences, Год журнала: 2023, Номер 80(5)

Опубликована: Апрель 24, 2023

Язык: Английский

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Biological importance of arginine: A comprehensive review of the roles in structure, disorder, and functionality of peptides and proteins

International Journal of Biological Macromolecules, Год журнала: 2023, Номер 257, С. 128646 - 128646

Опубликована: Дек. 6, 2023

Язык: Английский

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AlphaFold-Multimer accurately captures interactions and dynamics of intrinsically disordered protein regions

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(44)

Опубликована: Окт. 24, 2024

Interactions mediated by intrinsically disordered protein regions (IDRs) pose formidable challenges in structural characterization. IDRs are highly versatile, capable of adopting diverse structures and engagement modes. Motivated recent strides structure prediction, we embarked on exploring the extent to which AlphaFold-Multimer can faithfully reproduce intricacies interactions involving IDRs. To this end, gathered multiple datasets covering versatile spectrum IDR binding modes used them probe AlphaFold-Multimer’s prediction their dynamics. Our analyses revealed that is not only predicting various types bound with high success rate, but distinguishing true from decoys, unreliable predictions accurate ones achievable appropriate use intrinsic scores. We found quality drops for more heterogeneous, fuzzy interaction types, most likely due lower interface hydrophobicity higher coil content. Notably though, certain scores, such as Predicted Aligned Error residue-ipTM, correlated heterogeneity IDR, enabling clear distinctions between homogeneous Finally, our benchmarking also be successful when using full-length proteins, cognate facilitate identification a given partner, established “minD,” pinpoints potential sites protein. study demonstrates correctly identify interacting predict mode partner.

Язык: Английский

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KaMLs for Predicting Protein pK_a Values and Ionization States: Are Trees All You Need?

Journal of Chemical Theory and Computation, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

Despite its importance in understanding biology and computer-aided drug discovery, the accurate prediction of protein ionization states remains a formidable challenge. Physics-based approaches struggle to capture small, competing contributions complex environment, while machine learning (ML) is hampered by scarcity experimental data. Here, we report development pKa ML (KaML) models based on decision trees graph attention networks (GAT), exploiting physicochemical new experiment database (PKAD-3) enriched with highly shifted pKa's. KaML-CBtree significantly outperforms current state art predicting values across all six titratable amino acids, notably achieving predictions for deprotonated cysteines lysines─a blind spot previous models. The superior performance KaMLs achieved part through several innovations, including separate treatment acid base, data augmentation using AlphaFold structures, model pretraining theoretical database. We also introduce classification protonation as metric evaluating A meta-feature analysis suggests possible reason lightweight tree outperform more deep GAT. release an end-to-end predictor PKAD-3 database, which facilitates variety applications provides foundation further advances electrostatic research.

Язык: Английский

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Citrullination of TDP-43 is a key post-translation modification associated with structural and functional changes and progressive pathology in TDP-43 mouse models and human proteinopathies

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 2, 2025

Abstract TAR DNA-binding protein 43 (TDP-43) pathology is associated with a spectrum of clinical dementias including limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC). Post-translational modifications (PTM) are linked to toxic gain-of-function and cytoplasmic aggregation 1–3 . Phosphorylation remains the most investigated PTM standard criterion for determining progression subclassification in proteinopathies 4–7 However, full PTMs on structure biology remain unknown. Utilizing mass-spectrometry analysis we identified citrullination as novel irreversible “bona-fide” protein. We recognized peptidyl arginine deiminase 2 4 (PAD2 PAD4) mediate conversion (R) citrulline (citR) vitro demonstrated increased PAD2 PAD4 expression human wildtype mouse model (Tg (Thy1-TARDBP4). Transmission electron microscopy imaging revealed induced vast structural while ThT altered kinetics citrullinated further provided mechanistic evidence reduced electrostatic pi-pi interactions citR Low Complexity Domain (LCD) RNA, favoring liquid-solid phase separation condensate formation. Generation validation several specific antibodies against epitopes epitope domain-specific effects solubility vivo Importantly, found distinct reactivities shedding light into contribution epitope-specific properties pathological assemblies brain tissue from LATE-NC, or without comorbid Alzheimer’s disease neuropathologic (ADNC). These findings unique look temporal signatures, potential relevance pure LATE-NC ADNC + LATE-NC. Collectively, these data reveal existence at targeted sites via PAD2/PAD4 activities, presenting critical step proteinopathy.

Язык: Английский

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Biomolecular condensates: insights into early and late steps of the HIV-1 replication cycle

Retrovirology, Год журнала: 2023, Номер 20(1)

Опубликована: Апрель 7, 2023

Abstract A rapidly evolving understanding of phase separation in the biological and physical sciences has led to redefining virus-engineered replication compartments many viruses with RNA genomes. Condensation viral, host genomic subgenomic RNAs can take place evade innate immunity response help viral replication. Divergent prompt liquid–liquid (LLPS) invade cell. During HIV there are several steps involving LLPS. In this review, we characterize ability individual partners that assemble into biomolecular condensates (BMCs). Of note, bioinformatic analyses predict models line published observations. Importantly, BMCs contribute function key retroviral For example, reverse transcription takes within nuclear BMCs, called HIV-MLOs while during late steps, nucleocapsid acts as a driver or scaffold recruit client components aid assembly progeny virions. Overall, LLPS infections represents newly described event now appreciated virology field, also be considered an alternative pharmacological target current drug therapies especially when become resistant antiviral treatment.

Язык: Английский

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Molecular genomic insights into melanoma associated proteins PRAME and BAP1

Journal of Biomolecular Structure and Dynamics, Год журнала: 2025, Номер unknown, С. 1 - 31

Опубликована: Март 14, 2025

Melanoma, a globally prevalent skin cancer with over 325,000 new cases annually, necessitates comprehensive under- standing of its molecular components. This study looks at the PRAME (cutaneous melanoma-associated antigen) and BAP1 (gene controlling gene-environment interactions) proteins. Both are associated critical genomic alterations that significantly influence melanoma progression patient outcomes. is overexpressed in various cancers, especially uveal (UM), where high levels correlate poor prognosis instability linked to chromosome 8q12 alterations. Meanwhile, mutations contribute increased higher risk metastasis UM, highlighting importance as key prognostic marker tumorigenesis. Established approaches along features proposed this work used investigate sequence conservation, polyglutamic acid presence, intrinsic disorder proteins, polar-nonpolar residues arrangement conserved highlight their roles protein function interaction. Sequence invariance indicates possibility functional relevance evolutionary conservation. has enhanced flexibility, whereas changed disorder-promoting residue sequences. Polyglutamic strings found both emphasizing modulatory involvement interactions. The ratios spatial amino acids have profound on interactions gene dysregulation. contributes better knowledge two proteins viz. by unraveling structural complexities.

Язык: Английский

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The distal-proximal relationships among the human moonlighting proteins: Evolutionary hotspots and Darwinian checkpoints

International Journal of Biological Macromolecules, Год журнала: 2024, Номер 259, С. 128998 - 128998

Опубликована: Янв. 3, 2024

Язык: Английский

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On the Roles of Protein Intrinsic Disorder in the Origin of Life and Evolution

Life, Год журнала: 2024, Номер 14(10), С. 1307 - 1307

Опубликована: Окт. 15, 2024

Obviously, the discussion of different factors that could have contributed to origin life and evolution is clear speculation, since there no way checking validity most related hypotheses in practice, as corresponding events not only already happened, but took place a very distant past. However, are few undisputable facts present at moment, such existence wide variety living forms abundant presence intrinsically disordered proteins (IDPs) or hybrid containing ordered domains regions (IDRs) all forms. Since it seems currently existing originated from common ancestor, their result evolution. Therefore, one ask logical question what role(s) structureless highly dynamic vastly multifunctional IDPs/IDRs might This study represents an attempt consider various ideas pertaining potential roles protein intrinsic disorder

Язык: Английский

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