The ribonucleoprotein hnRNPA1 mediates RNA and DNA telomeric G-quadruplexes through an RGG-rich region

Journal of Biological Chemistry, Год журнала: 2025, Номер unknown, С. 108491 - 108491

Опубликована: Апрель 1, 2025

hnRNPA1, a protein from the heterogeneous-nuclear ribonucleoprotein family, mediates cellular processes such as RNA metabolism and DNA telomere maintenance. Besides folded recognition motifs, hnRNPA1 has ∼135 amino-acids long low-complexity domain (LCD) consisting of an RGG-rich region prion-like (PrLD). Biochemical data suggest that modulates G-quadruplexes (GQs) in telomeric repeats. Here, we utilize in-house developed replica exchange technique (REHT) to generate heterogeneous conformational ensemble hnRNPA1-RGG explore its functional significance Single chain statistics abundance structural well consistency with experimentally reported faithful recapitulation local interactions. We also introduce protocol functionally significant IDP-nucleic acid complex structures corroborate experimental knowledge their binding. find RGG-box preferentially binds grooves loops GQs providing specificity towards certain GQ sequence secondary structures. Turn-like expose Phe promote stacking G-tetrads, while Tyr Asn residues form essential hydrogen bonds electrostatic Several these were identified important by earlier HSQC chemical shift data. Our binding simulation studies reveal minor population can perturb structure, which likely expedites unfolding activities hnRNPA1-UP1 at end.

Язык: Английский

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Predicting Conformational Ensembles of Intrinsically Disordered Proteins: From Molecular Dynamics to Machine Learning

The Journal of Physical Chemistry Letters, Год журнала: 2024, Номер 15(32), С. 8177 - 8186

Опубликована: Авг. 2, 2024

Intrinsically disordered proteins and regions (IDP/IDRs) are ubiquitous across all domains of life. Characterized by a lack stable tertiary structure, IDP/IDRs populate diverse set transiently formed structural states that can promiscuously adapt upon binding with specific interaction partners and/or certain alterations in environmental conditions. This malleability is foundational for their role as tunable hubs core cellular processes such signaling, transcription, translation. Tracing the conformational ensemble an IDP/IDR its perturbation response to regulatory cues thus paramount illuminating function. However, heterogeneity poses several challenges. Here, we review experimental computational methods devised disentangle landscape IDP/IDRs, highlighting recent advances permit proteome-wide scans conformations. We briefly evaluate selected using N-terminal human copper transporter 1 test case outline further challenges prediction.

Язык: Английский

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Atomistic molecular dynamics simulations of intrinsically disordered proteins

Current Opinion in Structural Biology, Год журнала: 2025, Номер 92, С. 103029 - 103029

Опубликована: Март 10, 2025

Язык: Английский

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Noncovalent Lasso Entanglements are Common in Experimentally Derived Intrinsically Disordered Protein Ensembles and Strongly Influenced by Protein Length and Charge

The Journal of Physical Chemistry B, Год журнала: 2025, Номер unknown

Опубликована: Май 3, 2025

Noncovalent lasso entanglements are conformations in which a protein backbone segment forms loop closed by noncovalent interactions and that is threaded one or more times either the N- C-terminal of both. While these common globular proteins, their presence intrinsically disordered proteins regions (IDPs/IDRs) remains largely unexplored. Here, we examine whether IDPs/IDRs monomeric form populate how sequence length charge composition influence entanglement prevalence. Using experimentally derived IDP/IDR ensembles from Protein Ensemble Database, find 48% (199 416) its entries contain subpopulations with entangled conformations, 25% having conformational 50% entangled. This includes IDPs such as nuclear pore complex Nup153, nonstructural V Hendra virus, Eukaryotic initiation factor 4F subunit p150. molecular simulations, (i) most prevalent weak polyampholytes polyelectrolytes, strong but rare polyelectrolytes; (ii) populations increase IDP length; (iii) probability positively correlates chain compaction; (iv) human proteome exhibit conformations. A GO enrichment analysis reveals function subcellular localization. Thus, findings indicate widespread structural feature have potential to be biologically relevant.

Язык: Английский

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Assessing the helical stability of polyXYs at the boundaries of Intrinsically Disordered Regions with MD simulations

Deleted Journal, Год журнала: 2025, Номер unknown, С. 100054 - 100054

Опубликована: Май 1, 2025

Язык: Английский

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Elucidating the conformational change of dengue envelope protein using the Markov state model

Molecular Simulation, Год журнала: 2024, Номер 50(15), С. 1153 - 1169

Опубликована: Авг. 6, 2024

Dengue virus, an arbovirus of genus flavivirus, is one the most prevalent infectious disease causing organisms in tropical environment leading to numerous deaths every year. The envelope protein plays a crucial role viral genome entry into host cell. This achieved through structure and oligomeric status change dengue protein. pre-fusion post-fusion states' structures are known although pathway intermediate involved this process have remained dark till date. In study, we used targeted molecular dynamics (MD) simulation followed by conventional MD Markov state model analysis elucidate conformation from state. Intermediate conformations which may future serve as therapeutic targets also been deduced model. determination pave way for design transition analog inhibitors prevent virus changing its thus establishing infection. results obtained could lead development novel drugs combat

Язык: Английский

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Weighted families of contact maps to characterize conformational ensembles of (highly-)flexible proteins

Bioinformatics, Год журнала: 2024, Номер 40(11)

Опубликована: Окт. 21, 2024

Abstract Motivation Characterizing the structure of flexible proteins, particularly within realm intrinsic disorder, presents a formidable challenge due to their high conformational variability. Currently, structural representation relies on (possibly large) ensembles derived from combination experimental and computational methods. The detailed analysis these is difficult task, for which existing tools have limited effectiveness. Results This study proposes an innovative extension concept contact maps ensemble framework, incorporating probabilistic nature disordered proteins. Within this characterized through weighted family maps. To achieve this, conformations are first described using refined definition that appropriately accounts geometry inter-residue interactions sequence context. Representative features naturally emerge subsequent clustering resulting contact-based descriptors. Importantly, transiently populated readily identified large ensembles. performance method illustrated by several use cases compared with other approaches, highlighting its superiority in capturing relevant highly Availability implementation An open-source provided together easy-to-use Jupyter notebook, available at https://gitlab.laas.fr/moma/WARIO.

Язык: Английский

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Towards accurate, force field independent conformational ensembles of intrinsically disordered proteins

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

Опубликована: Окт. 5, 2024

Abstract Determining accurate atomic resolution conformational ensembles of intrinsically disordered proteins (IDPs) is extremely challenging. Molecular dynamics (MD) simulations provide atomistic IDPs, but their accuracy highly dependent on the quality physical models, or force fields, used. Here, we demonstrate how to determine IDPs by integrating all-atom MD with experimental data from nuclear magnetic resonance (NMR) spectroscopy and small-angle x-ray scattering (SAXS) a simple, robust fully automated maximum entropy reweighting procedure. We that when this approach applied sufficient data, IDP derived different fields converge similar distributions. The procedure presented here facilitates integration extensive datasets enables calculation accurate, force-field independent IDPs.

Язык: Английский

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Molecular Mechanisms Underlying the Loop-Closing Dynamics of β-1,4 Galactosyltransferase 1

Journal of Chemical Information and Modeling, Год журнала: 2024, Номер 65(1), С. 390 - 401

Опубликована: Дек. 31, 2024

The β-1,4 galactosylation catalyzed by galactosyltransferases (β4Gal-Ts) is not only closely associated with diverse physiological and pathological processes in humans but also widely applied the N-glycan modification of protein glycoengineering. loop-closing process β4Gal-Ts an essential intermediate step intervening binding events donor substrate (UDP-Gal/Mn2+) acceptor during its catalytic cycle, a significant impact on activities. However, molecular mechanisms regulating dynamics are entirely clear. Here, we construct Markov state models (MSMs) based approximately 20 μs all-atom simulations to explore for galactosyltransferase 1 (β4Gal-T1). Our MSM reveals five key metastable states β4Gal-T1 upon binding, indicating that entire conformational transition occurs time scale ∼10 μs. Moreover, regulatory mechanism involving six conserved residues (R187, H190, F222, W310, I341, D346) among validated account C-loop W-loop site-directed mutagenesis enzymatic activity assays, exhibiting high consistency our computational predictions. Overall, research proposes detailed atomic-level insight into β4Gal-T1, contributing deeper understanding galactosylation.

Язык: Английский

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Targeted Stochastic Gradient MCMC for HMMs with Rare Latent States

Bayesian Analysis, Год журнала: 2024, Номер -1(-1)

Опубликована: Янв. 1, 2024

Язык: Английский

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