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.

scholarly journals Why do eukaryotic proteins contain more intrinsically disordered regions?

2018 ◽  
Author(s):  
Walter Basile ◽  
Marco Salvatore ◽  
Claudio Bassot ◽  
Arne Elofsson
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Intrinsic Disorder ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Significant Difference ◽  
Eukaryotic Proteins ◽  
The Difference ◽  
Almost All ◽  
Disordered Regions

AbstractIntrinsic disorder is much more abundant in eukaryotic than in prokaryotic proteins. However, the reason behind this is unclear. It has been proposed that the disordered regions are functionally important for regulation in eukaryotes, but it has also been proposed that the difference is a result of lower selective pressure in eukaryotes. Almost all studies intrinsic disorder is predicted from the amino acid sequence of a protein. Therefore, there should exist an underlying difference in the amino acid distributions between eukaryotic and prokaryotic proteins causing the predicted difference in intrinsic disorder. To obtain a better understanding of why eukaryotic proteins contain more intrinsically disordered regions we compare proteins from complete eukaryotic and prokaryotic proteomes.Here, we show that the difference in intrinsic disorder origin from differences in the linker regions. Eukaryotic proteins have more extended linker regions and, in particular, the eukaryotic linker regions are more disordered. The average eukaryotic protein is about 500 residues long; it contains 250 residues in linker regions, of which 80 are disordered. In comparison, prokaryotic proteins are about 350 residues long and only have 100-110 residues in linker regions, and less than 10 of these are intrinsically disordered.Further, we show that there is no systematic increase in the frequency of disorder-promoting residues in eukaryotic linker regions. Instead, the difference in frequency of only three amino acids seems to lie behind the difference. The most significant difference is that eukaryotic linkers contain about 9% serine, while prokaryotic linkers have roughly 6.5%. Eukaryotic linkers also contain about 2% more proline and 2-3% fewer isoleucine residues. The reason why primarily these amino acids vary in frequency is not apparent, but it cannot be excluded that the difference is serine is related to the increased need for regulation through phosphorylation and that the proline difference is related to increase of eukaryotic specific repeats.

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 Intrinsic Disorder in Tetratricopeptide Repeat Proteins

2020 ◽  
Vol 21 (10) ◽  
pp. 3709 ◽  
Author(s):  
Nathan W. Van Bibber ◽  
Cornelia Haerle ◽  
Roy Khalife ◽  
Bin Xue ◽  
Vladimir N. Uversky
Keyword(s):  
Protein Interactions ◽  
Posttranslational Modifications ◽  
Tandem Repeats ◽  
Intrinsically Disordered Protein ◽  
Intrinsic Disorder ◽  
Protein Protein Interactions ◽  
Systematic Analysis ◽  
Tetratricopeptide Repeats ◽  
Intrinsically Disordered ◽  
Tetratricopeptide Repeat Proteins

Among the realm of repeat containing proteins that commonly serve as “scaffolds” promoting protein-protein interactions, there is a family of proteins containing between 2 and 20 tetratricopeptide repeats (TPRs), which are functional motifs consisting of 34 amino acids. The most distinguishing feature of TPR domains is their ability to stack continuously one upon the other, with these stacked repeats being able to affect interaction with binding partners either sequentially or in combination. It is known that many repeat-containing proteins are characterized by high levels of intrinsic disorder, and that many protein tandem repeats can be intrinsically disordered. Furthermore, it seems that TPR-containing proteins share many characteristics with hybrid proteins containing ordered domains and intrinsically disordered protein regions. However, there has not been a systematic analysis of the intrinsic disorder status of TPR proteins. To fill this gap, we analyzed 166 human TPR proteins to determine the degree to which proteins containing TPR motifs are affected by intrinsic disorder. Our analysis revealed that these proteins are characterized by different levels of intrinsic disorder and contain functional disordered regions that are utilized for protein-protein interactions and often serve as targets of various posttranslational modifications.

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.

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.

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 Intrinsic disorder codes for leaps of protein expression

2020 ◽  
Author(s):  
Chi-Ning Chuang ◽  
Tai-Ting Woo ◽  
Shih-Ying Tsai ◽  
Wan-Chen Li ◽  
Chia-Ling Chen ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Folding ◽  
Protein Expression ◽  
Posttranslational Modifications ◽  
Protein Quality ◽  
Intrinsic Disorder ◽  
Protein Homeostasis ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Regulate Protein

AbstractIntrinsically disordered regions (IDRs) are protein sequences lacking fixed or ordered three-dimensional structures. Many IDRs are endowed with important molecular functions such as physical interactions, posttranslational modifications or solubility enhancement. We reveal that several biologically important IDRs can act as N-terminal fusion carriers to promote target protein folding or protein quality control, thereby enhancing protein expression. This nanny function has a reasonably strong correlation with high S/T/Q/N amino acid content in IDRs and it is tunable (e.g., via phosphorylation) to regulate protein homeostasis. We propose a hypothesis that “N-terminal intrinsic disorder facilitates abundance” (NIDFA) to explain how some yeast proteins use their N-terminal IDRs (N-IDRs) to generate high levels of protein product. These N-IDRs are versatile toolkits for functional divergence in signaling and evolution.SignificanceDisorder within an otherwise well-structured protein is mostly found in intrinsically disordered regions (IDRs). IDRs can provide many advantages to proteins, including: (1) mediating protein-protein or protein-peptide interactions by adopting different conformations; (2) facilitating protein regulation via diverse posttranslational modifications; and (3) regulating the half-lives of proteins that have been targeted for proteasomal degradation. Here, we report that several biologically important IDRs in S. cerevisiae can act as N-terminal fusion carriers to promote target protein folding or protein quality control, thereby enhancing protein expression. We demonstrate by genetic and bioinformatic analyses that this nanny function is well correlated with high content of serine, threonine, glutamine and asparagine in IDRs and is tunable (e.g., via phosphorylation) to regulate protein homeostasis.

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