Poised PABP–RNA hubs implement signal-dependent mRNA decay in development

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(9), P. 1439 - 1447

Published: July 25, 2024

Abstract Signaling pathways drive cell fate transitions largely by changing gene expression. However, the mechanisms for rapid and selective transcriptome rewiring in response to signaling cues remain elusive. Here we use deep learning deconvolve both sequence determinants trans -acting regulators that trigger extracellular signal-regulated kinase (ERK)–mitogen-activated protein (MEK)-induced decay of naive pluripotency mRNAs. Timing is coupled embryo implantation through ERK–MEK phosphorylation LIN28A, which repositions pLIN28A highly A+U-rich 3′ untranslated region (3′UTR) termini Interestingly, these 3′UTR serve as poly(A)-binding (PABP)-binding hubs, poised signal-induced convergence with LIN28A. The multivalency AUU motifs determines efficacy pLIN28A–PABP convergence, enhances PABP binding, decreases protection poly(A) tails activates mRNA enable progression toward primed pluripotency. Thus, LIN28A PABP–RNA hubs drives selection mRNAs decay, enabling remodeling ensures swift developmental progression.

Language: Английский

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Intrinsic Disorder and Phase Separation Coordinate Exocytosis, Motility, and Chromatin Remodeling in the Human Acrosomal Proteome

Proteomes, Journal Year: 2025, Volume and Issue: 13(2), P. 16 - 16

Published: April 28, 2025

Intrinsic disorder refers to protein regions that lack a fixed three−dimensional structure under physiological conditions, enabling conformational plasticity. This flexibility allows for diverse functions, including transient interactions, signaling, and phase separation via disorder-to-order transitions upon binding. Our study focused on investigating the role of intrinsic liquid−liquid (LLPS) in human acrosome, sperm-specific organelle essential fertilization. Using computational prediction models, network analysis, Structural Classification Proteins (SCOP) functional assessments, Gene Ontology, we analyzed 250 proteins within acrosomal proteome. bioinformatic analysis yielded 97 with high levels (>30%) structural disorder. Further enrichment identified associations between disordered overlapping SCOP domains critical processes, vesicle trafficking, membrane fusion, enzymatic activation. Examples include PLC-like phosphodiesterase domain, t-SNARE P-domain calnexin/calreticulin. Protein–protein interaction networks revealed as hubs tightly interconnected systems, emphasizing their importance. LLPS propensity modeling determined over 30% these are high-probability drivers (>60%), underscoring dynamic compartmentalization. such myristoylated alanine-rich C-kinase substrate nuclear transition 2 exhibited both propensities A significant relationship (p < 0.0001, R² = 0.649) was observed level propensity, showing facilitating separation. Overall, findings provide insights into how contribute adaptability precision required fertilization, implications understanding disorders associated acrosome reaction.

Language: Английский

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Virus-modified paraspeckle-like condensates are hubs for viral RNA processing and their formation drives genomic instability

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 26, 2024

Abstract The nucleus is a highly organised yet dynamic environment containing distinct membraneless nuclear bodies. This spatial separation enables subset of components to be concentrated within biomolecular condensates, allowing efficient and discrete processes occur which regulate cellular function. One such body, paraspeckles, are comprised multiple paraspeckle proteins (PSPs) built around the architectural RNA, NEAT1_2 . Paraspeckle function fully elucidated but has been implicated in variety developmental disease scenarios. We demonstrate that Kaposi’s sarcoma-associated herpesvirus (KSHV) drives formation structurally paraspeckles with dramatically increased size altered protein composition required for productive lytic replication. highlight these virus-modified form adjacent virus replication centres, potentially functioning as RNA processing hubs viral transcripts during infection. Notably, we reveal PSP sequestration into result genome instability both KSHV Epstein Barr (EBV) infection, implicating their virus-mediated tumourigenesis.

Language: Английский

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Evolution of Virus-like Features and Intrinsically Disordered Regions in Retrotransposon-derived Mammalian Genes

Molecular Biology and Evolution, Journal Year: 2024, Volume and Issue: 41(8)

Published: Aug. 1, 2024

Abstract Several mammalian genes have originated from the domestication of retrotransposons, selfish mobile elements related to retroviruses. Some proteins encoded by these maintained virus-like features; including self-processing, capsid structure formation, and generation different isoforms through −1 programmed ribosomal frameshifting. Using quantitative approaches in molecular evolution biophysical analyses, we studied 28 retrotransposon-derived genes, with a focus on features. By analyzing rate synonymous substitutions, show that frameshifting mechanism three (PEG10, PNMA3, PNMA5) is conserved across mammals originates alternative proteins. These were targets positive selection primates, one positively selected sites affects B-cell epitope spike domain PNMA5 capsid, finding reminiscent observations infectious viruses. More generally, found vary their intrinsically disordered region content this directly associated evolutionary rates. Most are located regions some them impact protein posttranslational modifications, such as autocleavage phosphorylation. Detailed analyses properties showed preferentially targeted lower conformational entropy. Furthermore, introduces variation binary sequence patterns orthologues, well chain compaction. Our results shed light trajectories unique class suggest novel approach study how characteristics affected evolution.

Language: Английский

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Advances in the structure and function of the nucleolar protein fibrillarin

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: Nov. 13, 2024

Fibrillarin (FBL) is a highly conserved and well-researched nucleolar protein found in eukaryotes. Its presence was first identified 1985 through immunoblotting analyses using antisera from patients with autoimmune scleroderma. Through immunoelectron microscopy, FBL shown to be localized the dense fibrillar component of nucleolus, leading term "fibrillarin". The composed 321 amino acids contains two significant functional domains: GAR domain methyltransferase domain. It expressed nucleolus This makes one most studied proteins. While methylation not essential for cell survival, gene crucial eukaryotic cells, underscoring importance investigating additional functions that do rely on methylation. review will primarily examine structural domains its classic activity. Additionally, our eukaryote-specific regulating intracellular phase separation. Furthermore, this paper analyzes recent developments utilization study pathogen infections cancer research over past decade.

Language: Английский

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Identification of an intrinsically disordered region (IDR) in arginyltransferase 1 (ATE1)

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 24, 2024

Arginyltransferase 1 (ATE1) catalyzes arginylation, an important post-translational modification (PTM) in eukaryotes that plays a critical role cellular homeostasis. The disruption of ATE1 function is implicated mammalian neurodegenerative disorders and cardiovascular maldevelopment, while arginylation has also been linked to the activities several human viruses such as SARS-CoV-2 HIV. Despite known significance function, past biophysical studies this enzyme have mainly focused on yeast ATE1, leaving mechanism cells unclear. In study, we sought structurally biophysically characterize mouse (

Language: Английский

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Identification of an Intrinsically Disordered Region (IDR) in Arginyltransferase 1 (ATE1)

Biochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 6, 2024

Arginyltransferase 1 (ATE1) catalyzes arginylation, an important posttranslational modification (PTM) in eukaryotes that plays a critical role cellular homeostasis. The disruption of ATE1 function is implicated mammalian neurodegenerative disorders and cardiovascular maldevelopment, while arginylation has also been linked to the activities several human viruses such as SARS-CoV-2 HIV. Despite known significance function, past biophysical studies this enzyme have mainly focused on yeast ATE1, leaving mechanism cells unclear. In study, we sought structurally biophysically characterize mouse (Mus musculus) ATE1. Using size-exclusion chromatography (SEC), small-angle X-ray scattering (SAXS), hydrogen–deuterium exchange mass spectrometry (HDX-MS), assisted by AlphaFold modeling, found more complex than Importantly, our data indicate existence intrinsically disordered region (IDR) all splice variants. However, comparative HDX-MS analyses show does not IDR, consistent with prior X-ray, cryo-EM, SAXS analyses. Furthermore, bioinformatics approaches reveal sequences, well those large majority other eukaryotes, contain IDR-like sequence positioned proximity GNAT active-site fold. Computational analysis suggests IDR facilitates formation between tRNAArg, adding new complexity structure providing insights for future functions.

Language: Английский

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The role of RNA binding proteins in cancer biology: A focus on FMRP

Genes & Diseases, Journal Year: 2024, Volume and Issue: 12(4), P. 101493 - 101493

Published: Dec. 22, 2024

RNA-binding proteins (RBPs) act as crucial regulators of gene expression within cells, exerting precise control over processes such RNA splicing, transport, localization, stability, and translation through their specific binding to molecules. The diversity complexity RBPs are particularly significant in cancer biology, they directly impact a multitude metabolic events closely associated with tumor initiation progression. fragile X mental retardation protein (FMRP), member the RBP family, is central neurodevelopmental disorder syndrome increasingly recognized modulation biology its influence on metabolism. protein's versatility, stemming from diverse domains, enables it govern wide array transcript processing events. Modifications FMRP's or localization have been regulation mRNAs linked various pertinent cancer, including proliferation, metastasis, epithelial-mesenchymal transition, cellular senescence, chemotherapy/radiotherapy resistance, immunotherapy evasion. In this review, we emphasize recent findings analyses that suggest contrasting functions family tumorigenesis. Our knowledge regulated by FMRP rapidly growing, has led identification multiple targets for therapeutic intervention some which already moved into clinical trials practice.

Language: Английский

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