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 Assemblages: Functional units formed by cellular phase separation

2014 ◽  
Vol 206 (5) ◽  
pp. 579-588 ◽  
Author(s):  
Jeffrey A. Toretsky ◽  
Peter E. Wright
Keyword(s):  
Phase Separation ◽  
Intrinsically Disordered Proteins ◽  
Intrinsic Disorder ◽  
Low Complexity ◽  
Disordered Proteins ◽  
Intracellular Space ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disease States ◽  
Membrane Bound

The partitioning of intracellular space beyond membrane-bound organelles can be achieved with collections of proteins that are multivalent or contain low-complexity, intrinsically disordered regions. These proteins can undergo a physical phase change to form functional granules or other entities within the cytoplasm or nucleoplasm that collectively we term “assemblage.” Intrinsically disordered proteins (IDPs) play an important role in forming a subset of cellular assemblages by promoting phase separation. Recent work points to an involvement of assemblages in disease states, indicating that intrinsic disorder and phase transitions should be considered in the development of therapeutics.

scholarly journals New classification of intrinsic disorder in the Human proteome

2018 ◽  
Author(s):  
Antonio Deiana ◽  
Sergio Forcelloni ◽  
Alessandro Porrello ◽  
Andrea Giansanti
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Chemical Properties ◽  
Intrinsic Disorder ◽  
Disordered Proteins ◽  
General Category ◽  
Nucleic Acid Binding ◽  
Functional Protein ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions

ABSTRACTWe propose a new, sequence-only, classification of intrinsically disordered human proteins which is based on two parameters: dr, the percentage of disordered residues, and Ld, the length of the longest disordered segment in the sequence. Depending on dr and Ld, we distinguish five variants: i) ordered proteins (ORDs); ii) not disordered proteins (NDPsj; (iii) proteins with intrinsically disordered regions (PDRs); iv) intrinsically disordered proteins (IDPs) and v) proteins with fragmented disorder (FRAGs). PDRs have been considered in the general category of intrinsically disordered proteins for a long time. We show that PDRs are closer to globular, ordered proteins (ORDs and NDPs) than to disordered ones (IDPs), both in amino acid composition and functionally. Moreover, NDPs and PDRs are uniformly spread over several functional protein classes, whereas IDPs are concentrated only on two, namely nucleic acid binding proteins and transcription factors, which are just a subset of the functions that are commonly associated with protein intrinsic disorder. As a conclusion, PDRs and IDPs should be considered, in future classifications, as distinct variants of disordered proteins, with different physical-chemical properties and functional spectra.

scholarly journals Seeing Keratinocyte Proteins through the Looking Glass of Intrinsic Disorder

2021 ◽  
Vol 22 (15) ◽  
pp. 7912
Author(s):  
Rambon Shamilov ◽  
Victoria L. Robinson ◽  
Brian J. Aneskievich
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Amino Acid Content ◽  
Intrinsic Disorder ◽  
Low Complexity ◽  
Disordered Proteins ◽  
Keratinocyte Differentiation ◽  
Compositional Bias ◽  
Light Microscope Level ◽  
Intrinsically Disordered ◽  
Looking Glass

Epidermal keratinocyte proteins include many with an eccentric amino acid content (compositional bias), atypical ultrastructural fate (built-in protease sensitivity), or assembly visible at the light microscope level (cytoplasmic granules). However, when considered through the looking glass of intrinsic disorder (ID), these apparent oddities seem quite expected. Keratinocyte proteins with highly repetitive motifs are of low complexity but high adaptation, providing polymers (e.g., profilaggrin) for proteolysis into bioactive derivatives, or monomers (e.g., loricrin) repeatedly cross-linked to self and other proteins to shield underlying tissue. Keratohyalin granules developing from liquid–liquid phase separation (LLPS) show that unique biomolecular condensates (BMC) and proteinaceous membraneless organelles (PMLO) occur in these highly customized cells. We conducted bioinformatic and in silico assessments of representative keratinocyte differentiation-dependent proteins. This was conducted in the context of them having demonstrated potential ID with the prospect of that characteristic driving formation of distinctive keratinocyte structures. Intriguingly, while ID is characteristic of many of these proteins, it does not appear to guarantee LLPS, nor is it required for incorporation into certain keratinocyte protein condensates. Further examination of keratinocyte-specific proteins will provide variations in the theme of PMLO, possibly recognizing new BMC for advancements in understanding intrinsically disordered proteins as reflected by keratinocyte biology.

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 The Mysterious Unfoldome: Structureless, Underappreciated, Yet Vital Part of Any Given Proteome

2010 ◽  
Vol 2010 ◽  
pp. 1-14 ◽  
Author(s):  
Vladimir N. Uversky
Keyword(s):  
Large Scale ◽  
Intrinsically Disordered Proteins ◽  
Biologically Active ◽  
Disordered Proteins ◽  
Unfolded Proteins ◽  
Intrinsically Disordered ◽  
Proteome Level ◽  
Natively Unfolded ◽  
Natively Unfolded Proteins

Contrarily to the general believe, many biologically active proteins lack stable tertiary and/or secondary structure under physiological conditions in vitro. These intrinsically disordered proteins (IDPs) are highly abundant in nature and many of them are associated with various human diseases. The functional repertoire of IDPs complements the functions of ordered proteins. Since IDPs constitute a significant portion of any given proteome, they can be combined in an unfoldome; which is a portion of the proteome including all IDPs (also known as natively unfolded proteins, therefore, unfoldome), and describing their functions, structures, interactions, evolution, and so forth. Amino acid sequence and compositions of IDPs are very different from those of ordered proteins, making possible reliable identification of IDPs at the proteome level by various computational means. Furthermore, IDPs possess a number of unique structural properties and are characterized by a peculiar conformational behavior, including their high stability against low pH and high temperature and their structural indifference toward the unfolding by strong denaturants. These peculiarities were shown to be useful for elaboration of the experimental techniques for the large-scale identification of IDPs in various organisms. Some of the computational and experimental tools for the unfoldome discovery are discussed in this review.

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.

scholarly journals Avoiding Regions Symptomatic of Conformational and Functional Flexibility to Identify Antiviral Targets in Current and Future Coronaviruses

2016 ◽  
Vol 8 (11) ◽  
pp. 3471-3484 ◽  
Author(s):  
Jordon Rahaman ◽  
Jessica Siltberg-Liberles
Keyword(s):  
Secondary Structure ◽  
Structure Prediction ◽  
Secondary Structure Prediction ◽  
Nonstructural Protein ◽  
Intrinsic Disorder ◽  
Sequence Motif ◽  
Protein Families ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Antiviral Targets

Abstract Within the last 15 years, two related coronaviruses (Severe Acute Respiratory Syndrome [SARS]-CoV and Middle East Respiratory Syndrome [MERS]-CoV) expanded their host range to include humans, with increased virulence in their new host. Coronaviruses were recently found to have little intrinsic disorder compared with many other virus families. Because intrinsically disordered regions have been proposed to be important for rewiring interactions between virus and host, we investigated the conservation of intrinsic disorder and secondary structure in coronaviruses in an evolutionary context. We found that regions of intrinsic disorder are rarely conserved among different coronavirus protein families, with the primary exception of the nucleocapsid. Also, secondary structure predictions are only conserved across 50–80% of sites for most protein families, with the implication that 20–50% of sites do not have conserved secondary structure prediction. Furthermore, nonconserved structure sites are significantly less constrained in sequence divergence than either sites conserved in the secondary structure or sites conserved in loop. Avoiding regions symptomatic of conformational flexibility such as disordered sites and sites with nonconserved secondary structure to identify potential broad-specificity antiviral targets, only one sequence motif (five residues or longer) remains from the >10,000 starting sites across all coronaviruses in this study. The identified sequence motif is found within the nonstructural protein (NSP) 12 and constitutes an antiviral target potentially effective against the present day and future coronaviruses. On shorter evolutionary timescales, the SARS and MERS clades have more sequence motifs fulfilling the criteria applied. Interestingly, many motifs map to NSP12 making this a prime target for coronavirus antivirals.

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.

scholarly journals A New Census of Protein Tandem Repeats and Their Relationship with Intrinsic Disorder

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 407 ◽  
Author(s):  
Matteo Delucchi ◽  
Elke Schaper ◽  
Oxana Sachenkova ◽  
Arne Elofsson ◽  
Maria Anisimova
Keyword(s):  
Structural Organization ◽  
Tandem Repeats ◽  
State Of The Art ◽  
Intrinsic Disorder ◽  
Prediction Methods ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Protein Length ◽  
Positive Linear Correlation ◽  
The Difference

Protein tandem repeats (TRs) are often associated with immunity-related functions and diseases. Since that last census of protein TRs in 1999, the number of curated proteins increased more than seven-fold and new TR prediction methods were published. TRs appear to be enriched with intrinsic disorder and vice versa. The significance and the biological reasons for this association are unknown. Here, we characterize protein TRs across all kingdoms of life and their overlap with intrinsic disorder in unprecedented detail. Using state-of-the-art prediction methods, we estimate that 50.9% of proteins contain at least one TR, often located at the sequence flanks. Positive linear correlation between the proportion of TRs and the protein length was observed universally, with Eukaryotes in general having more TRs, but when the difference in length is taken into account the difference is quite small. TRs were enriched with disorder-promoting amino acids and were inside intrinsically disordered regions. Many such TRs were homorepeats. Our results support that TRs mostly originate by duplication and are involved in essential functions such as transcription processes, structural organization, electron transport and iron-binding. In viruses, TRs are found in proteins essential for virulence.

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