Intrinsically disordered proteins in cellular signalling and regulation

Nature Reviews Molecular Cell Biology, Journal Year: 2014, Volume and Issue: 16(1), P. 18 - 29

Published: Dec. 22, 2014

Language: Английский

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Classification of Intrinsically Disordered Regions and Proteins

Chemical Reviews, Journal Year: 2014, Volume and Issue: 114(13), P. 6589 - 6631

Published: April 29, 2014

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTClassification of Intrinsically Disordered Regions and ProteinsRobin van der Lee*†‡, Marija Buljan†, Benjamin Lang†, Robert J. Weatheritt†, Gary W. Daughdrill§, A. Keith Dunker∥, Monika Fuxreiter⊥, Julian Gough#, Joerg Gsponer∇, David T. Jones○, Philip M. Kim◆¶⊕, Richard Kriwacki∀, Christopher Oldfield∥, Rohit V. Pappu&, Peter Tompa@$, Vladimir N. Uversky%★, E. Wright□, Madan Babu*†View Author Information† MRC Laboratory Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom‡ Centre for Biomolecular Informatics, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands§ Department Cell Microbiology, South Florida, 3720 Spectrum Boulevard, Suite 321, Tampa, Florida 33612, States∥ Biochemistry Indiana School Medicine, Indianapolis, 46202, States⊥ MTA-DE Momentum Protein Dynamics, Debrecen, H-4032 Nagyerdei krt 98, Hungary# Computer Science, Bristol, Merchant Venturers Building, Bristol BS8 1UB, Kingdom∇ High-Throughput British Columbia, Vancouver, Columbia V6T 1Z4, Canada○ Bioinformatics Group, College London, WC1E 6BT, Kingdom◆ ¶ ⊕ ◆Terrence Donnelly Cellular Research, ¶Department Genetics, ⊕Department Toronto, Ontario M5S 3E1, Canada∀ Structural St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, States& Biomedical Engineering Center Biological Systems Engineering, Washington in Louis, Missouri 63130, States@ VIB Vrije Universiteit Brussel, Brussels, Belgium$ Institute Enzymology, Natural Sciences, Hungarian Academy Budapest, Hungary% Medicine USF Health Byrd Alzheimer’s Institute, Morsani States★ Instrumentation, Russian Pushchino, Moscow Region, Russia□ Integrative Computational Biology Skaggs Chemical Scripps 10550 North Torrey Pines Road, La Jolla, California 92037, States*E-mail: [email protected]*E-mail: protected]Cite this: Chem. Rev. 2014, 114, 13, 6589–6631Publication Date (Web):April 29, 2014Publication History Received23 September 2013Published online29 April 2014Published inissue 9 July 2014https://doi.org/10.1021/cr400525mCopyright © 2014 American SocietyRIGHTS & PERMISSIONSACS AuthorChoiceArticle Views45196Altmetric-Citations1295LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum full text article downloads since November 2008 (both PDF HTML) across all institutions individuals. These metrics regularly updated to reflect usage leading up last few days.Citations number other articles citing this article, calculated by Crossref daily. Find more information about citation counts.The Altmetric Attention Score is a quantitative measure attention that research has received online. Clicking on donut icon will load page at altmetric.com with additional details score social media presence given article. how calculated. Share Add toView InAdd Full Text ReferenceAdd Description ExportRISCitationCitation abstractCitation referencesMore Options onFacebookTwitterWechatLinked InReddit (22 MB) Get e-AlertscloseSUBJECTS:Diseases disorders,Genetics,Monomers,Peptides proteins,Protein structure e-Alerts

Language: Английский

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The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease

Biochemical Society Transactions, Journal Year: 2016, Volume and Issue: 44(5), P. 1185 - 1200

Published: Oct. 15, 2016

In the 1960s, Christian Anfinsen postulated that unique three-dimensional structure of a protein is determined by its amino acid sequence. This work laid foundation for sequence–structure–function paradigm, which states sequence determines structure, and function. However, class polypeptide segments called intrinsically disordered regions does not conform to this postulate. review, I will first describe established emerging ideas about how contribute then discuss molecular principles regulatory mechanisms, such as alternative splicing asymmetric localization transcripts encode regions, can increase functional versatility proteins. Finally, human disease emergence cellular complexity during organismal evolution.

Language: Английский

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Markov State Models Provide Insights into Dynamic Modulation of Protein Function

Accounts of Chemical Research, Journal Year: 2015, Volume and Issue: 48(2), P. 414 - 422

Published: Jan. 3, 2015

ConspectusProtein function is inextricably linked to protein dynamics. As we move from a static structural picture dynamic ensemble view of structure and function, novel computational paradigms are required for observing understanding conformational dynamics proteins its functional implications. In principle, molecular simulations can provide the time evolution atomistic models proteins, but long scales associated with make it difficult observe rare dynamical transitions. The issue extracting essential components noisy simulation data presents another set challenges in obtaining an unbiased motions. Therefore, methodology that provides statistical framework efficient sampling human-readable key aspects analysis required. Markov state model (MSM), which has recently become popular worldwide studying dynamics, example such framework.In this Account, review use hierarchy automatic identification states, degrees freedom slow processes. Applications MSMs scale phenomena as activation mechanisms cellular signaling yielded insights into function. particular, built using large-scale GPCRs kinases, have shown complex changes be described terms motifs or "molecular switches" within protein, transitions between functionally active inactive states proceed via multiple pathways, ligand substrate binding modulates flux through these pathways. Finally, also theoretical toolbox effect nonequilibrium perturbations on Considering vivo occur under conditions, coupled mechanics way connect their environments. Nonequilibrium folding reveal presence dynamically frozen glass-like landscape. These observed rich β-sheets, indicates possible role nucleation β-sheet aggregates those amyloid-fibril formation. describe how been used understand behavior intrinsically disordered amyloid-β, human islet amyloid polypeptide, p53. While certainly not panacea rigorous foundation entropically dominated processes convenient lens viewing

Language: Английский

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ALS-Causing Mutations Significantly Perturb the Self-Assembly and Interaction with Nucleic Acid of the Intrinsically Disordered Prion-Like Domain of TDP-43

PLoS Biology, Journal Year: 2016, Volume and Issue: 14(1), P. e1002338 - e1002338

Published: Jan. 6, 2016

TAR-DNA-binding protein-43 (TDP-43) C-terminus encodes a prion-like domain widely presented in RNA-binding proteins, which functions to form dynamic oligomers and also, amazingly, hosts most amyotrophic lateral sclerosis (ALS)-causing mutations. Here, as facilitated by our previous discovery, circular dichroism (CD), fluorescence nuclear magnetic resonance (NMR) spectroscopy, we have successfully determined conformations, dynamics, self-associations of the full-length domains wild type three ALS-causing mutants (A315E, Q331K, M337V) both aqueous solutions membrane environments. The study decodes following: (1) TDP-43 is intrinsically disordered only with some nascent secondary structures solutions, but owns capacity assemble into rich β-sheet structures. By contrast, despite having highly similar gained ability amyloid oligomers. all formed fibrils after incubation imaged electron microscopy. (2) interaction nucleic acid enhances self-assembly for triggers quick aggregation mutants. (3) A membrane-interacting subdomain has been identified over residues Met311-Gln343 indispensable neurotoxicity, transforms well-folded Ω-loop-helix structure Furthermore, very membrane-embedded will undergo further self-association environment. Our implies that appears an energy landscape, allows assembly wild-type sequence under limited condition sets, point mutations are sufficient remodel it more favor formation or irreversible aggregation, thus supporting emerging view pathologic may occur via exaggeration functionally important assemblies. coupled critically account its high therefore decoupling represent promising therapeutic strategy treat causing neurodegenerative diseases.

Language: Английский

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Intrinsically Disordered Proteins: An Overview

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(22), P. 14050 - 14050

Published: Nov. 14, 2022

Many proteins and protein segments cannot attain a single stable three-dimensional structure under physiological conditions; instead, they adopt multiple interconverting conformational states. Such intrinsically disordered or are highly abundant across proteomes, involved in various effector functions. This review focuses on different aspects of regions, which form the basis so-called “Disorder–function paradigm” proteins. Additionally, experimental approaches computational tools used for characterizing regions discussed. Finally, role diseases their utility as potential drug targets explored.

Language: Английский

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NMR Provides Unique Insight into the Functional Dynamics and Interactions of Intrinsically Disordered Proteins

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(10), P. 9331 - 9356

Published: April 21, 2022

Intrinsically disordered proteins are ubiquitous throughout all known proteomes, playing essential roles in aspects of cellular and extracellular biochemistry. To understand their function, it is necessary to determine structural dynamic behavior describe the physical chemistry interaction trajectories. Nuclear magnetic resonance perfectly adapted this task, providing ensemble averaged parameters that report on each assigned molecule, unveiling otherwise inaccessible insight into reaction kinetics thermodynamics for function. In review, we recent applications NMR-based approaches understanding conformational energy landscape, nature time scales local long-range dynamics how they depend environment, even cell. Finally, illustrate ability NMR uncover mechanistic basis functional molecular assemblies important human health.

Language: Английский

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Eukaryotic transcription factors: paradigms of protein intrinsic disorder

Biochemical Journal, Journal Year: 2017, Volume and Issue: 474(15), P. 2509 - 2532

Published: July 12, 2017

Gene-specific transcription factors (TFs) are key regulatory components of signaling pathways, controlling, for example, cell growth, development, and stress responses. Their biological functions determined by their molecular structures, as exemplified structured DNA-binding domains targeting specific cis-acting elements in genes, the significant lack fixed tertiary structure extensive intrinsically disordered regions. Recent research protein intrinsic disorder (ID) has changed our understanding transcriptional activation from 'negative noodles' to ID regions with function-related, short sequence motifs recognition features structural propensities. This review focuses on aspects TFs, which represent paradigms ID-related features. Through examples, we how ID-associated flexibility TFs enables them participate large interactomes, they use only a few hydrophobic residues, motifs, prestructured coupled folding binding interactions co-activators, accessibility post-translational modification affects interactions. It is furthermore emphasized classic biochemical concepts like allostery, conformational selection, induced fit, feedback regulation undergoing revival appreciation ID. The also describes most recent advances based computational simulations ID-based interaction mechanisms analysis context full-length suggests future directions TF

Language: Английский

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Structural Basis for the Interaction of a Human Small Heat Shock Protein with the 14-3-3 Universal Signaling Regulator

Structure, Journal Year: 2017, Volume and Issue: 25(2), P. 305 - 316

Published: Jan. 12, 2017

Language: Английский

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Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells

Science, Journal Year: 2018, Volume and Issue: 362(6417), P. 952 - 956

Published: Oct. 25, 2018

Transforming growth factor-β1 (TGF-β1) is one of very few cytokines produced in a latent form, requiring activation to exert any its vastly diverse effects on development, immunity, and cancer. Regulatory T cells (Tregs) suppress immune within close proximity by activating TGF-β1 presented GARP (glycoprotein A repetitions predominant) integrin αVβ8 their surface. We solved the crystal structure GARP:latent bound an antibody that stabilizes complex blocks release active TGF-β1. This finding reveals how exploits unusual medley interactions, including fold complementation amino terminus TGF-β1, chaperone orient cytokine for binding αVβ8. Thus, this work further elucidates mechanism antibody-mediated blockade immunosuppression Tregs.

Language: Английский

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