ALS mutations in the TIA-1 prion-like domain trigger highly condensed pathogenic structures

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(38)

Published: Sept. 16, 2022

T cell intracellular antigen-1 (TIA-1) plays a central role in stress granule (SG) formation by self-assembly via the prion-like domain (PLD). In TIA-1 PLD, amino acid mutations associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) or Welander distal myopathy (WDM), have been identified. However, how these affect PLD properties has remained elusive. this study, we uncovered implicit pathogenic structures caused mutations. NMR analysis indicated that dynamic of are synergistically determined physicochemical acids units five residues. Molecular dynamics simulations and three-dimensional electron crystallography, together biochemical assays, revealed WDM mutation E384K attenuated sticky properties, whereas ALS P362L A381T enhanced inducing β-sheet interactions highly condensed assembly, respectively. These results suggest increase likelihood irreversible amyloid fibrillization after phase-separated droplet formation, process may lead to pathogenicity.

Language: Английский

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Representing structures of the multiple conformational states of proteins

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 83, P. 102703 - 102703

Published: Sept. 28, 2023

Biomolecules exhibit dynamic behavior that single-state models of their structures cannot fully capture. We review some recent advances for investigating multiple conformations biomolecules, including experimental methods, molecular dynamics simulations, and machine learning. also address the challenges associated with representing single- multiple-state in data archives, a particular focus on NMR structures. Establishing standardized representations annotations will facilitate effective communication understanding these complex to broader scientific community.

Language: Английский

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NMR spectroscopic investigations of transition metal complexes in organometallic and bioinorganic chemistry

Bulletin of the Korean Chemical Society, Journal Year: 2024, Volume and Issue: 45(7), P. 593 - 613

Published: May 28, 2024

Abstract The field of coordination chemistry has evolved to intersect with organic and biochemistry, giving rise the disciplines organometallic bioinorganic chemistry. Nuclear magnetic resonance (NMR) spectroscopy can be applied for characterizing transition metal complexes, spanning both diamagnetic paramagnetic complexes prevalent in compounds metalloproteins. This review offers a comprehensive overview wide variety characterization techniques, ranging from basic 1 H 13 C NMR advanced methods such as heteronuclear experiments, polarization transfer relaxometry, multidimensional spectroscopy. diverse array spectroscopic outlined here promises enhance our comprehension facilitating development innovative catalysts therapeutics.

Language: Английский

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Structural studies of protein–nucleic acid complexes: A brief overview of the selected techniques

Computational and Structural Biotechnology Journal, Journal Year: 2023, Volume and Issue: 21, P. 2858 - 2872

Published: Jan. 1, 2023

Protein-nucleic acid complexes are involved in all vital processes, including replication, transcription, translation, regulation of gene expression and cell metabolism. Knowledge the biological functions molecular mechanisms beyond activity macromolecular can be determined from their tertiary structures. Undoubtably, performing structural studies protein-nucleic is challenging, mainly because these types often unstable. In addition, individual components may display extremely different surface charges, causing to precipitate at higher concentrations used many studies. Due variety biophysical properties, no simple universal guideline exists that helps scientists chose a method successfully determine structure specific complex. this review, we provide summary following experimental methods, which applied study structures complexes: X-ray neutron crystallography, nuclear magnetic resonance (NMR) spectroscopy, cryogenic electron microscopy (cryo-EM), atomic force (AFM), small angle scattering (SAS) circular dichroism (CD) infrared (IR) spectroscopy. Each discussed regarding its historical context, advancements over past decades recent years, weaknesses strengths. When single does not satisfactory data on selected complex, combination several methods should considered as hybrid approach; thus, problems solved when studying complexes.

Language: Английский

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Multivalent interactions of the disordered regions of XLF and XRCC4 foster robust cellular NHEJ and drive the formation of ligation-boosting condensates in vitro

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(11), P. 1732 - 1744

Published: June 19, 2024

Language: Английский

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

The Journal of Physical Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(32), P. 8177 - 8186

Published: Aug. 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.

Language: Английский

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Conformations, interactions and functions of intrinsically disordered syndecans

Biochemical Society Transactions, Journal Year: 2023, Volume and Issue: 51(3), P. 1083 - 1096

Published: June 19, 2023

Syndecans are transmembrane heparan sulfate proteoglycans present on most mammalian cell surfaces. They have a long evolutionary history, single syndecan gene being expressed in bilaterian invertebrates. attracted interest because of their potential roles development and disease, including vascular diseases, inflammation various cancers. Recent structural data is providing important insights into functions, which complex, involving both intrinsic signaling through cytoplasmic binding partners co-operative mechanisms where syndecans form nexus with other receptors such as integrins tyrosine kinase growth factor receptors. While the domain syndecan-4 has well-defined dimeric structure, ectodomains intrinsically disordered, linked to capacity interact multiple partners. However, it remains fully establish impact glycanation partner proteins core protein conformations. Genetic models indicate that conserved property links cytoskeleton calcium channels transient receptor class, compatible mechanosensors. In turn, influence actin organization motility, adhesion extracellular matrix environment. Syndecan clustering surface microdomains relevance tissue differentiation development, for example stem cells, but also disease expression can be markedly up-regulated. Since diagnostic prognostic markers well possible targets some forms cancer, unravel structure/function relationships four syndecans.

Language: Английский

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Sensitivity-enhanced NMR 15N R1 and R1ρ relaxation experiments for the investigation of intrinsically disordered proteins at high magnetic fields

Methods, Journal Year: 2024, Volume and Issue: 223, P. 1 - 15

Published: Jan. 17, 2024

NMR relaxation experiments provide residue-specific insights into the structural dynamics of proteins. Here, we present an optimized set sensitivity-enhanced

Language: Английский

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Probing the dynamic landscape of peptides in molecular assemblies by synergized NMR experiments and MD simulations

Communications Chemistry, Journal Year: 2024, Volume and Issue: 7(1)

Published: Feb. 13, 2024

Peptides or proteins containing small biomolecular aggregates, such as micelles, bicelles, droplets and nanodiscs, are pivotal in many fields ranging from structural biology to pharmaceutics. Monitoring dynamics of systems has been limited by the lack experimental methods that could directly detect their fast (picosecond nanosecond) timescale dynamics. Spin relaxation times NMR experiments sensitive motions, but interpretation for aggregates is not straightforward. Here we show dynamic landscape peptide-containing molecular assemblies can be determined a synergistic combination solution state (MD) simulations. Solution straightforward implement without an excessive amount sample, while direct spin data MD simulations enables landscapes peptides other aggregated molecules. To demonstrate this, interpret transmembrane, peripheral, tail anchored embedded micelles. Our results indicate detergent molecules do rotate together rigid body, viscous medium composed micelle. also provide indirect information on peptide conformational ensembles. This work gives new perspectives complex assemblies.

Language: Английский

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Invited review: Modeling milk stability

Journal of Dairy Science, Journal Year: 2024, Volume and Issue: 107(8), P. 5259 - 5279

Published: March 23, 2024

Novel insights into the stability of milk and products during storage processing result from describing caseins near neutral pH as hydrophilic, intrinsically disordered, proteins. Casein solubility is strongly influenced by multivalent ion binding. Solubility high at a or above, but decreases casein net charge approaches zero, allowing condensed phase gel to form, then increases lower pH. Of particular importance for micelle proportion free in (i.e., not bound directly nanoclusters calcium phosphate). Free are more soluble better able act molecular chaperones (to prevent whey protein aggregation) than caseins. Some highly phosphorylated can also mineral inhibit growth phosphate phases mineralized deposits forming on membranes heat exchangers. Thus, reduced when bind amyloid fibrils, destabilized proteins phosphate. The multivalent-binding model quantitatively describes these other factors affecting manufacture storage.

Language: Английский

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