Functional roles of intrinsic disorder in CRISPR-associated protein Cas9

2017 ◽  
Vol 13 (9) ◽  
pp. 1770-1780 ◽  
Author(s):  
Zhihua Du ◽  
Vladimir N. Uversky
Keyword(s):  
Dna Binding ◽  
Intrinsic Disorder ◽  
Dna Binding Proteins ◽  
Functional Roles ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
P Protein ◽  
Protein Intrinsic Disorder ◽  
Rna And Dna ◽  
Different Origin

Protein intrinsic disorder is an important characteristic commonly detected in multifunctional or RNA- and DNA-binding proteins. We show here that the CRISPR-associated Cas9 proteins of different origin contain functionally important intrinsically disordered regions.

Troponins, intrinsic disorder, and cardiomyopathy

2016 ◽  
Vol 397 (8) ◽  
pp. 731-751 ◽  
Author(s):  
Insung Na ◽  
Min J. Kong ◽  
Shelby Straight ◽  
Jose R. Pinto ◽  
Vladimir N. Uversky
Keyword(s):  
Posttranslational Modifications ◽  
Cardiac Troponin ◽  
Troponin I ◽  
Troponin T ◽  
Intrinsic Disorder ◽  
Functional Changes ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Structural And Functional Properties ◽  
Protein Intrinsic Disorder

Abstract Cardiac troponin is a dynamic complex of troponin C, troponin I, and troponin T (TnC, TnI, and TnT, respectively) found in the myocyte thin filament where it plays an essential role in cardiac muscle contraction. Mutations in troponin subunits are found in inherited cardiomyopathies, such as hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). The highly dynamic nature of human cardiac troponin and presence of numerous flexible linkers in its subunits suggest that understanding of structural and functional properties of this important complex can benefit from the consideration of the protein intrinsic disorder phenomenon. We show here that mutations causing decrease in the disorder score in TnI and TnT are significantly more abundant in HCM and DCM than mutations leading to the increase in the disorder score. Identification and annotation of intrinsically disordered regions in each of the troponin subunits conducted in this study can help in better understanding of the roles of intrinsic disorder in regulation of interactomes and posttranslational modifications of these proteins. These observations suggest that disease-causing mutations leading to a decrease in the local flexibility of troponins can trigger a whole plethora of functional changes in the heart.

Eukaryotic transcription factors: paradigms of protein intrinsic disorder

2017 ◽  
Vol 474 (15) ◽  
pp. 2509-2532 ◽  
Author(s):  
Lasse Staby ◽  
Charlotte O'Shea ◽  
Martin Willemoës ◽  
Frederik Theisen ◽  
Birthe B. Kragelund ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Stress Responses ◽  
Tertiary Structure ◽  
Intrinsic Disorder ◽  
Molecular Structures ◽  
Sequence Motifs ◽  
Short Sequence ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Protein Intrinsic Disorder

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

scholarly journals Evidence for DNA-mediated nuclear compartmentalization distinct from phase separation

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
David Trombley McSwiggen ◽  
Anders S Hansen ◽  
Sheila S Teves ◽  
Hervé Marie-Nelly ◽  
Yvonne Hao ◽  
...  
Keyword(s):  
Phase Separation ◽  
Dna Binding ◽  
Rna Polymerase Ii ◽  
Protein Interactions ◽  
Binding Proteins ◽  
Dna Binding Proteins ◽  
Pol Ii ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Simplex Virus

RNA Polymerase II (Pol II) and transcription factors form concentrated hubs in cells via multivalent protein-protein interactions, often mediated by proteins with intrinsically disordered regions. During Herpes Simplex Virus infection, viral replication compartments (RCs) efficiently enrich host Pol II into membraneless domains, reminiscent of liquid-liquid phase separation. Despite sharing several properties with phase-separated condensates, we show that RCs operate via a distinct mechanism wherein unrestricted nonspecific protein-DNA interactions efficiently outcompete host chromatin, profoundly influencing the way DNA-binding proteins explore RCs. We find that the viral genome remains largely nucleosome-free, and this increase in accessibility allows Pol II and other DNA-binding proteins to repeatedly visit nearby DNA binding sites. This anisotropic behavior creates local accumulations of protein factors despite their unrestricted diffusion across RC boundaries. Our results reveal underappreciated consequences of nonspecific DNA binding in shaping gene activity, and suggest additional roles for chromatin in modulating nuclear function and organization.

scholarly journals Critical Assessment of Protein Intrinsic Disorder Prediction

2020 ◽  
Author(s):  
Marco Necci ◽  
Damiano Piovesan ◽  
Silvio C.E. Tosatto ◽  
◽  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Intrinsic Disorder ◽  
Critical Assessment ◽  
Disordered Proteins ◽  
Blind Test ◽  
Disorder Prediction ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Binding Regions ◽  
Protein Intrinsic Disorder

AbstractIntrinsically disordered proteins defying the traditional protein structure-function paradigm represent a challenge to study experimentally. As a large part of our knowledge rests on computational predictions, it is crucial for their accuracy to be high. The Critical Assessment of protein Intrinsic Disorder prediction (CAID) experiment was established as a community-based blind test to determine the state of the art in predicting intrinsically disordered regions in proteins and the subset of disordered residues involved in binding other molecules. A total of 43 methods, 32 for disorder and 11 for binding regions, were evaluated on a dataset of 646 novel manually curated proteins from DisProt. The best methods use deep learning techniques and significantly outperform widely used earlier physicochemical methods across different types of targets. Disordered binding regions remain hard to predict correctly. Depending on the definition used, the top disorder predictor has an FMax of 0.483 (DisProt) or 0.792 (DisProt-PDB). As the top binding predictor only attains an FMax of 0.231, this suggests significant potential for improvement. Intriguingly, computing times among the top performing methods vary by up to four orders of magnitude.

Conformational heterogeneity in tails of DNA-binding proteins is augmented by proline containing repeats

2017 ◽  
Vol 13 (12) ◽  
pp. 2531-2544
Author(s):  
Harshavardhan Khare ◽  
Debayan Dey ◽  
Chilakapati Madhu ◽  
Dillip Senapati ◽  
Srinivasarao Raghothama ◽  
...  
Keyword(s):  
Dna Binding ◽  
Binding Proteins ◽  
Intrinsic Disorder ◽  
Dna Binding Proteins ◽  
Conformational Heterogeneity ◽  
Intrinsically Disordered ◽  
Disordered Peptides

We model intrinsically disordered peptides mimicking the tails of DNA-binding proteins and propose parameters for the design of intrinsic disorder.

scholarly journals Critical assessment of protein intrinsic disorder prediction

2021 ◽  
Author(s):  
Marco Necci ◽  
◽  
Damiano Piovesan ◽  
Silvio C. E. Tosatto ◽  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Intrinsic Disorder ◽  
Critical Assessment ◽  
Disordered Proteins ◽  
Blind Test ◽  
Disorder Prediction ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Full Dataset ◽  
Protein Intrinsic Disorder

AbstractIntrinsically disordered proteins, defying the traditional protein structure–function paradigm, are a challenge to study experimentally. Because a large part of our knowledge rests on computational predictions, it is crucial that their accuracy is high. The Critical Assessment of protein Intrinsic Disorder prediction (CAID) experiment was established as a community-based blind test to determine the state of the art in prediction of intrinsically disordered regions and the subset of residues involved in binding. A total of 43 methods were evaluated on a dataset of 646 proteins from DisProt. The best methods use deep learning techniques and notably outperform physicochemical methods. The top disorder predictor has Fmax = 0.483 on the full dataset and Fmax = 0.792 following filtering out of bona fide structured regions. Disordered binding regions remain hard to predict, with Fmax = 0.231. Interestingly, computing times among methods can vary by up to four orders of magnitude.

Visualising intrinsic disorder and conformational variation in protein ensembles

2014 ◽  
Vol 169 ◽  
pp. 179-193 ◽  
Author(s):  
Julian Heinrich ◽  
Michael Krone ◽  
Seán I. O'Donoghue ◽  
Daniel Weiskopf
Keyword(s):  
Intrinsic Disorder ◽  
Molecular Graphics ◽  
Post Translational Modifications ◽  
3D Structures ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Wide Range ◽  
Conformational Variations ◽  
Protein Ensembles ◽  
Traditional Approaches

Intrinsically disordered regions (IDRs) in proteins are still not well understood, but are increasingly recognised as important in key biological functions, as well as in diseases. IDRs often confound experimental structure determination—however, they are present in many of the available 3D structures, where they exhibit a wide range of conformations, from ill-defined and highly flexible to well-defined upon binding to partner molecules, or upon post-translational modifications. Analysing such large conformational variations across ensembles of 3D structures can be complex and difficult; our goal in this paper is to improve this situation by augmenting traditional approaches (molecular graphics and principal components) with methods from human–computer interaction and information visualisation, especially parallel coordinates. We present a new tool integrating these approaches, and demonstrate how it can dissect ensembles to reveal functional insights into conformational variation and intrinsic disorder.

scholarly journals Intrinsic disorder in biomarkers of insulin resistance, hypoadiponectinemia, and endothelial dysfunction among the type 2 diabetic patients

2015 ◽  
Author(s):  
Osama H. Jiffri ◽  
Fadwa M. Al-Sharif ◽  
Essam H. Jiffri ◽  
Vladimir N. Uversky
Keyword(s):  
Insulin Resistance ◽  
Endothelial Dysfunction ◽  
Adhesion Molecule ◽  
Intrinsic Disorder ◽  
Cellular Adhesion ◽  
Diabetic Patients ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Cellular Adhesion Molecule

Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease that is strongly associated with the all-cause and cardiovascular mortality. The present study aimed to analyze the abundance and functionality of intrinsically disordered regions in several biomarkers of insulin resistance, adiponectin, and endothelial dysfunction found in the T2DM patients. In fact, in comparison to controls, obese T2DM patients are known to have significantly higher levels of inter-cellular adhesion molecule (iCAM-1), vascular cell adhesion molecule (vCAM-1), and E-selectin, whereas their adiponectin levels are relatively low. Bioinformatics analysis revealed that these selected biomarkers (iCAM-1, vCAM-1, E-selectin, and adiponectin) are characterized by the noticeable levels of intrinsic disorder propensity and high binding promiscuity, which are important features expected for proteins serving as biomarkers. Within the limit of studied groups, there is an association between insulin resistance and both hypoadiponectinemia and endothelial dysfunction.

MobiDB-lite 3.0: fast consensus annotation of intrinsic disorder flavors in proteins

2020 ◽  
Author(s):  
Marco Necci ◽  
Damiano Piovesan ◽  
Damiano Clementel ◽  
Zsuzsanna Dosztányi ◽  
Silvio C E Tosatto
Keyword(s):  
Large Scale ◽  
Theoretical Models ◽  
Intrinsic Disorder ◽  
Low Complexity ◽  
Compositional Bias ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Proteome Level ◽  
And Performance

Abstract Motivation The earlier version of MobiDB-lite is currently used in large-scale proteome annotation platforms to detect intrinsic disorder. However, new theoretical models allow for the classification of intrinsically disordered regions into subtypes from sequence features associated with specific polymeric properties or compositional bias. Results MobiDB-lite 3.0 maintains its previous speed and performance but also provides a finer classification of disorder by identifying regions with characteristics of polyolyampholytes, positive or negative polyelectrolytes, low-complexity regions or enriched in cysteine, proline or glycine or polar residues. Subregions are abundantly detected in IDRs of the human proteome. The new version of MobiDB-lite represents a new step for the proteome level analysis of protein disorder. Availability and implementation Both the MobiDB-lite 3.0 source code and a docker container are available from the GitHub repository:https://github.com/BioComputingUP/MobiDB-lite

scholarly journals Intrinsically Disordered Regions of the DNA-Binding Domain of Human FoxP1 Facilitate Domain Swapping

2020 ◽  
Vol 432 (19) ◽  
pp. 5411-5429 ◽  
Author(s):  
Exequiel Medina ◽  
Pablo Villalobos ◽  
George L. Hamilton ◽  
Elizabeth A. Komives ◽  
Hugo Sanabria ◽  
...  
Keyword(s):  
Dna Binding ◽  
Binding Domain ◽  
Domain Swapping ◽  
Dna Binding Domain ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Regions
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