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

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

Published: Feb. 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.

Language: Английский

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Conformational ensembles of the human intrinsically disordered proteome: Bridging chain compaction with function and sequence conservation

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

Published: May 8, 2023

Abstract Intrinsically disordered proteins and regions (collectively IDRs) are pervasive across proteomes in all kingdoms of life, help shape biological functions, involved numerous diseases. IDRs populate a diverse set transiently formed structures, yet defy commonly held sequence-structure-function relationships. Recent developments protein structure prediction have led to the ability predict three-dimensional structures folded at proteome scale, enabled large-scale studies structure-function In contrast, knowledge conformational properties is scarce, part because sequences poorly conserved only few been characterized experimentally. We developed an efficient model generate ensembles IDRs, thereby their from sequence only. Here, we applied this simulate human proteome. Examining 29,998 show how chain compaction correlated with cellular function localization, including different types biomolecular condensates. train use conservation structural orthologs. Our results recapitulate observations previous individual systems, enable us study relationship between sequence, conservation, ensembles, disease variants scale.

Language: Английский

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The impact of IDR phosphorylation on the RNA binding profiles of proteins

Trends in Genetics, Journal Year: 2024, Volume and Issue: 40(7), P. 580 - 586

Published: May 4, 2024

Language: Английский

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Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure

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

Published: March 27, 2024

Abstract The rationale for replacing the old binary of structure–function with trinity structure, disorder, and function has gained considerable ground in recent years. A continuum model based on expanded form existing paradigm can now subsume importance both conformational flexibility intrinsic disorder protein function. is actually critical understanding protein–protein interactions many regulatory processes, formation membrane‐less organelles, our revised notions specificity as amply illustrated by moonlighting proteins. While its amyloids prions often discussed, roles infectious diseases under extreme conditions are also becoming clear. This review an attempt to discuss how current function, specificity, evolution fit better model. integration structure a single may bring greater clarity continuing quest proteins molecular mechanisms their functionality.

Language: Английский

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Effects of Phosphorylation on Protein Backbone Dynamics and Conformational Preferences

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: 20(12), P. 4998 - 5011

Published: June 3, 2024

Phosphorylations are the most common and extensively studied post-translational modification (PTM) of proteins in eukaryotes. They constitute a major regulatory mechanism, modulating protein function, protein–protein interactions, as well subcellular localization. Phosphorylation sites preferably located intrinsically disordered regions have been shown to trigger structural rearrangements order-to-disorder transitions. can therefore significant effect on backbone dynamics or conformation, but only sparse experimental data available. To obtain more general description how when phosphorylations behavior, molecular (MD) currently provides suitable framework study these effects at large scale atomistic detail. This develops systematic MD simulation explore influence local conformational propensities proteins. Through series glycine-backbone peptides, we amino acid residues including three (Ser, Thr, Tyr), propensities. We further extended our investigate interactions all such between position i positions + 1, 2, 3, 4 peptides. The final set comprises ensembles for 3393 sequences with than 1 μs sampling each ensemble. validate relevance results, properties extracted from simulations compared NMR Biological Magnetic Resonance Data Bank. nature this enables projection gained knowledge onto any phosphorylation site proteome PTMs. full is publicly available, training reference set.

Language: Английский

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The effect of phosphorylation efficiency on the oncogenic properties of the protein E7 from high-risk HPV

Virus Research, Journal Year: 2024, Volume and Issue: 348, P. 199446 - 199446

Published: Aug. 14, 2024

The Human papillomavirus (HPV) causes tumors in part by hijacking the host cell cycle and forcing uncontrolled cellular division. While there are >200 genotypes of HPV, 15 classified as high-risk have been shown to transform infected cells contribute tumor formation. remaining low-risk not considered oncogenic result benign skin lesions. In oncoprotein E7 contributes dysregulation regulatory mechanisms. High-risk is phosphorylated at two conserved serine residues Casein Kinase 2 (CK2) this phosphorylation event increases binding affinity for proteins such suppressor retinoblastoma (pRb). possesses similar residues, it a lesser degree has decreased capabilities. When decreased, less able facilitate complex interactions between therefore capability dysregulate cycle. By comparing protein sequences from both low- HPV variants using site-directed mutagenesis combined with NMR spectroscopy cell-based assays, we demonstrate that presence key nonpolar valine within CK2 recognition sequence, present E7, reduces efficiency relative E7. This results significant loss ability degrade protein, thus also reducing increase proliferation reduce senescence. provides additional insight into differential E7-mediated outcomes when verses HPV. Understanding these differences may be important developing targeted treatment options HPV-induced cancers.

Language: Английский

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O-glycans Expand Lubricin and Attenuate Its Viscosity and Shear Thinning

Biomacromolecules, Journal Year: 2024, Volume and Issue: 25(7), P. 3893 - 3908

Published: May 30, 2024

Lubricin, an intrinsically disordered glycoprotein, plays a pivotal role in facilitating smooth movement and ensuring the enduring functionality of synovial joints. The central domain this protein serves as source excellent lubrication is characterized by its highly glycosylated, negatively charged, structure. However, influence O-glycans on viscosity lubricin remains unclear. In study, we employ molecular dynamics simulations absence presence shear, along with continuum simulations, to elucidate intricate interplay between impact lubricin's conformational properties viscosity. We found induce more extended conformation fragments region lubricin. These contribute reduction solution but at same time weaken shear thinning high rates, compared nonglycosylated systems density. This effect attributed steric electrostatic repulsion fragments, which prevents their conglomeration structuring. Our computational study yields mechanistic mechanism underlying previous experimental observations paves way rational understanding function fluid.

Language: Английский

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Phosphorylation patterns modulate the transient secondary structure of RNA polymerase II CTD without altering its global conformation

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

Published: Jan. 13, 2025

Abstract The intrinsically disordered C-terminal domain (CTD) of RNA polymerase II coordinates transcription and co-transcriptional events through dynamic phosphorylation patterns. While it has been long hypothesized that induces structural changes in the CTD, a direct comparison how different patterns modulate CTD conformation limited. Here, we generated two distinct an essential Drosophila region with kinase Dyrk1a: one where Ser2 are primarily phosphorylated, mimicking state near termination, hyperphosphorylation most Ser2, Ser5, Thr4 residues expanding on our work Ser5 phosphorylation, which mimics early elongation. Using 13 C Direct-Detect NMR, show tendency to form transient beta strands turns, is altered differently by phosphorylation. Small angle x-ray scattering (SAXS) revealed no significant global dimensions even at high levels contradicting common assumption phosphorylation-induced chain expansion. Our findings support model unphosphorylated adopts during pre-initiation. These structures disrupted elongation, later restored termination for recruiting turn-recognizing factors.

Language: Английский

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Theoretical evaluation of the biological activity of hydrogen

Medical Gas Research, Journal Year: 2025, Volume and Issue: 15(2), P. 266 - 275

Published: Jan. 18, 2025

Hydrogen (H 2 ), the simplest and most ubiquitous molecule in universe, has garnered significant scientific interest over past two decades because of its potential as an effective antioxidant anti-inflammatory agent. Traditionally considered inert, H is now being re-evaluated for unique bioactive properties. selectively neutralizes reactive oxygen nitrogen species, mitigating oxidative stress without disrupting essential cellular functions. This review therefore aims to provide a theoretical evaluation biological activity , focusing on pharmacokinetics, including absorption, distribution, retention within systems. The pharmacokinetic profile crucial understanding therapeutic applications. interaction with protein pockets particular interest, these sites may serve reservoirs or active influencing time. Additionally, impact signaling pathways, those regulating glucose metabolism responses, will be explored, offering insights into modulator metabolic redox homeostasis. Finally, interactions ferromagnetic molecules environments, well effects mechanisms, add another layer complexity role . By synthesizing current research, this seeks elucidate underlying mechanisms by which exert while also identifying critical areas further investigation. Understanding aspects fully characterizing pharmacodynamic assessing clinical treatment stress–related disorders.

Language: Английский

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Characteristic Fragmentation Behavior of Linear and Cyclic O-Linked Glycopeptides and Their Peptide Skeletons in MALDI-TOF/TOF MS

Molecules, Journal Year: 2025, Volume and Issue: 30(3), P. 711 - 711

Published: Feb. 5, 2025

Understanding characteristic post-source decay (PSD) fragmentation patterns in tandem mass spectrometry (MS/MS) is important for the identification of target molecules. In this study, we explored PSD associated with O-linked glycopeptides and their cyclization using MALDI-TOF/TOF MS analysis linear cyclic antifreeze glycoproteins. We performed a comparative proton sodium adduct ions peptide backbones glycoproteins, which have simple repeating sequence, shedding light on characteristics threonine side chain that its cyclized form. Furthermore, presence or absence glycan substitution serine caused changes fragmentation. These findings are expected to contribute prediction three-dimensional structures search physiologically active (glyco)peptides.

Language: Английский

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