NOT THAT RIGID MIDGETS AND NOT SO FLEXIBLE GIANTS: ON THE ABUNDANCE AND ROLES OF INTRINSIC DISORDER IN SHORT AND LONG PROTEINS

2012 ◽  
Vol 20 (04) ◽  
pp. 471-511 ◽  
Author(s):  
MARK HOWELL ◽  
RYAN GREEN ◽  
ALEXIS KILLEEN ◽  
LAMAR WEDDERBURN ◽  
VINCENT PICASCIO ◽  
...  
Keyword(s):  
Amino Acid ◽  
Intrinsically Disordered Proteins ◽  
Biological Activities ◽  
Intrinsic Disorder ◽  
Amino Acid Sequences ◽  
Disordered Proteins ◽  
Biological Functions ◽  
Intrinsically Disordered ◽  
Eukaryotic Proteins ◽  
Disordered Regions

Intrinsically disordered proteins or proteins with disordered regions are very common in nature. These proteins have numerous biological functions which are complementary to the biological activities of traditional ordered proteins. A noticeable difference in the amino acid sequences encoding long and short disordered regions was found and this difference was used in the development of length-dependent predictors of intrinsic disorder. In this study, we analyze the scaling of intrinsic disorder in eukaryotic proteins and investigate the presence of length-dependent functions attributed to proteins containing long disordered regions.

scholarly journals The Distinct Properties of the Consecutive Disordered Regions Inside or Outside Protein Domains and Their Functional Significance

2021 ◽  
Vol 22 (19) ◽  
pp. 10677
Author(s):  
Huqiang Wang ◽  
Haolin Zhong ◽  
Chao Gao ◽  
Jiayin Zang ◽  
Dong Yang
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Protein Domains ◽  
Comprehensive Analysis ◽  
Disordered Proteins ◽  
Functional Constraints ◽  
Biological Functions ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
And Function ◽  
Disordered Regions

The consecutive disordered regions (CDRs) are the basis for the formation of intrinsically disordered proteins, which contribute to various biological functions and increasing organism complexity. Previous studies have revealed that CDRs may be present inside or outside protein domains, but a comprehensive analysis of the property differences between these two types of CDRs and the proteins containing them is lacking. In this study, we investigated this issue from three viewpoints. Firstly, we found that in-domain CDRs are more hydrophilic and stable but have less stickiness and fewer post-translational modification sites compared with out-domain CDRs. Secondly, at the protein level, we found that proteins with only in-domain CDRs originated late, evolved rapidly, and had weak functional constraints, compared with the other two types of CDR-containing proteins. Proteins with only in-domain CDRs tend to be expressed spatiotemporal specifically, but they tend to have higher abundance and are more stable. Thirdly, we screened the CDR-containing protein domains that have a strong correlation with organism complexity. The CDR-containing domains tend to be evolutionarily young, or they changed from a domain without CDR to a CDR-containing domain during evolution. These results provide valuable new insights about the evolution and function of CDRs and protein domains.

scholarly journals Roles, Characteristics, and Analysis of Intrinsically Disordered Proteins: A Minireview

Life ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 320
Author(s):  
Frederik Lermyte
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Neurological Disorders ◽  
Intrinsically Disordered Proteins ◽  
Intrinsic Disorder ◽  
Disordered Proteins ◽  
Dynamic Nature ◽  
Intrinsically Disordered ◽  
Unfolded State ◽  
Underlying Causes

In recent years, there has been a growing understanding that a significant fraction of the eukaryotic proteome is intrinsically disordered, and that these conformationally dynamic proteins play a myriad of vital biological roles in both normal and pathological states. In this review, selected examples of intrinsically disordered proteins are highlighted, with particular attention for a few which are relevant in neurological disorders and in viral infection. Next, the underlying causes for intrinsic disorder are discussed, along with computational methods used to predict whether a given amino acid sequence is likely to adopt a folded or unfolded state in solution. Finally, biophysical methods for the analysis of intrinsically disordered proteins will be discussed, as well as the unique challenges they pose in this context due to their highly dynamic nature.

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.

scholarly journals Effects of Sequence Composition and Patterning on the Structure and Dynamics of Intrinsically Disordered Proteins

2020 ◽  
Author(s):  
Andrei Vovk ◽  
Anton Zilman
Keyword(s):  
Amino Acid ◽  
Intrinsically Disordered Proteins ◽  
Amino Acid Sequences ◽  
Coarse Grained ◽  
Disordered Proteins ◽  
Radius Of Gyration ◽  
Sequence Composition ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Polymer Models

AbstractUnlike the well defined structures of classical natively folded proteins, Intrinsically Disordered Proteins (IDP) and Intrinsically Disordered Regions (IDR) dynamically span large conformational and structural ensembles. This dynamic disorder impedes the study of the relationship between the amino acid sequences of the IDPs and their spatial structures, dynamics, and function. Multiple experimental and theoretical evidence points in many cases to the overall importance of the general properties of the amino acid sequence of the IPDs rather than their precise atomistic details. However, while different experimental techniques can probe aspects of the IDP conformations, often different techniques or conditions offer seemingly contradictory results. Using coarse-grained polymer models informed by experimental observations, we investigate the effects of several key variables on the dimensions and the dynamics of IDPs. The coarse-grained simulations are in a good agreement with the results of atomistic MD. We show that the sequence composition and patterning are well reflected in the global conformational variables such as the radius of gyration and hydrodynamic radius, while the end-to-end distance and dynamics are highly sequence specific. We identify the conditions that allow mapping of highly heterogeneous sequences of IDPs onto averaged minimal polymer models. We discuss the implications of these results for the interpretation of the recent experimental measurements, and for further development of appropriate mesoscopic models of IDPs.

scholarly journals Proteus: A Random Forest Classifier to Predict Disorder-to-Order Transitioning Binding Regions in Intrinsically Disordered Proteins

2016 ◽  
Author(s):  
Sankar Basu ◽  
Fredrik Söderquist ◽  
Björn Wallner
Keyword(s):  
Amino Acid ◽  
Random Forest ◽  
Amino Acid Sequence ◽  
Intrinsically Disordered Proteins ◽  
Random Forest Classifier ◽  
Amino Acid Sequences ◽  
Order Transition ◽  
Disordered Proteins ◽  
Data Set ◽  
Intrinsically Disordered

AbstractThe focus of the computational structural biology community has taken a dramatic shift over the past one-and-a-half decades from the classical protein structure prediction problem to the possible understanding of intrinsically disordered proteins (IDP) or proteins containing regions of disorder (IDPR). The current interest lies in the unraveling of a disorder-to-order transitioning code embedded in the amino acid sequences of IDPs / IDPRs. Disordered proteins are characterized by an enormous amount of structural plasticity which makes them promiscuous in binding to different partners, multi-functional in cellular activity and atypical in folding energy landscapes resembling partially folded molten globules. Also, their involvement in several deadly human diseases (e.g. cancer, cardiovascular and neurodegenerative diseases) makes them attractive drug targets, and important for a biochemical understanding of the disease(s). The study of the structural ensemble of IDPs is rather difficult, in particular for transient interactions. When bound to a structured partner, an IDPR adapts an ordered conformation in the complex. The residues that undergo this disorder-to-order transition are called protean residues, generally found in short contiguous stretches and the first step in understanding the modus operandi of an IDP / IDPR would be to predict these residues. There are a few available methods which predict these protean segments from their amino acid sequences; however, their performance reported in the literature leaves clear room for improvement. With this background, the current study presents 'Proteus', a random forest classifier that predicts the likelihood of a residue undergoing a disorder-to-order transition upon binding to a potential partner protein. The prediction is based on features that can be calculated using the amino acid sequence alone. Proteus compares favorably with existing methods predicting twice as many true positives as the second best method (55% vs. 27%) with a much higher precision on an independent data set. The current study also sheds some light on a possible 'disorder-to-order' transitioning consensus, untangled, yet embedded in the amino acid sequence of IDPs. Some guidelines have also been suggested for proceeding with a real-life structural modeling involving an IDPR using Proteus.Software Availabilityhttps://github.com/bjornwallner/proteus

scholarly journals Amino acid substitution scoring matrices specific to intrinsically disordered regions in proteins

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Rakesh Trivedi ◽  
Hampapathalu Adimurthy Nagarajaram
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Compositional Bias ◽  
Amino Acid Residues ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Scoring Matrices ◽  
Disordered Regions

Abstract An amino acid substitution scoring matrix encapsulates the rates at which various amino acid residues in proteins are substituted by other amino acid residues, over time. Database search methods make use of substitution scoring matrices to identify sequences with homologous relationships. However, widely used substitution scoring matrices, such as BLOSUM series, have been developed using aligned blocks that are mostly devoid of disordered regions in proteins. Hence, these substitution-scoring matrices are mostly inappropriate for homology searches involving proteins enriched with disordered regions as the disordered regions have distinct amino acid compositional bias, and therefore expected to have undergone amino acid substitutions that are distinct from those in the ordered regions. We, therefore, developed a novel series of substitution scoring matrices referred to as EDSSMat by exclusively considering the substitution frequencies of amino acids in the disordered regions of the eukaryotic proteins. The newly developed matrices were tested for their ability to detect homologs of proteins enriched with disordered regions by means of SSEARCH tool. The results unequivocally demonstrate that EDSSMat matrices detect more number of homologs than the widely used BLOSUM, PAM and other standard matrices, indicating their utility value for homology searches of intrinsically disordered proteins.

scholarly journals Intrinsically disordered proteins identified in the aggregate proteome serve as biomarkers of neurodegeneration

2021 ◽  
Author(s):  
Srinivas Ayyadevara ◽  
Akshatha Ganne ◽  
Meenakshisundaram Balasubramaniam ◽  
Robert J. Shmookler Reis
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Protein Complexes ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Physiological Processes ◽  
Protein Partners ◽  
And Function ◽  
Computational Analyses ◽  
Disordered Regions

AbstractA protein’s structure is determined by its amino acid sequence and post-translational modifications, and provides the basis for its physiological functions. Across all organisms, roughly a third of the proteome comprises proteins that contain highly unstructured or intrinsically disordered regions. Proteins comprising or containing extensive unstructured regions are referred to as intrinsically disordered proteins (IDPs). IDPs are believed to participate in complex physiological processes through refolding of IDP regions, dependent on their binding to a diverse array of potential protein partners. They thus play critical roles in the assembly and function of protein complexes. Recent advances in experimental and computational analyses predicted multiple interacting partners for the disordered regions of proteins, implying critical roles in signal transduction and regulation of biological processes. Numerous disordered proteins are sequestered into aggregates in neurodegenerative diseases such as Alzheimer’s disease (AD) where they are enriched even in serum, making them good candidates for serum biomarkers to enable early detection of AD.

scholarly journals Sequence Versus Composition: What Prescribes IDP Biophysical Properties?

Entropy ◽  
2019 ◽  
Vol 21 (7) ◽  
pp. 654 ◽  
Author(s):  
Jiří Vymětal ◽  
Jiří Vondrášek ◽  
Klára Hlouchová
Keyword(s):  
Amino Acid ◽  
Secondary Structure ◽  
Intrinsically Disordered Proteins ◽  
Random Sequence ◽  
Bioinformatic Analysis ◽  
Globular Proteins ◽  
Disordered Proteins ◽  
Compositional Bias ◽  
Intrinsically Disordered ◽  
Sequence Versus

Intrinsically disordered proteins (IDPs) represent a distinct class of proteins and are distinguished from globular proteins by conformational plasticity, high evolvability and a broad functional repertoire. Some of their properties are reminiscent of early proteins, but their abundance in eukaryotes, functional properties and compositional bias suggest that IDPs appeared at later evolutionary stages. The spectrum of IDP properties and their determinants are still not well defined. This study compares rudimentary physicochemical properties of IDPs and globular proteins using bioinformatic analysis on the level of their native sequences and random sequence permutations, addressing the contributions of composition versus sequence as determinants of the properties. IDPs have, on average, lower predicted secondary structure contents and aggregation propensities and biased amino acid compositions. However, our study shows that IDPs exhibit a broad range of these properties. Induced fold IDPs exhibit very similar compositions and secondary structure/aggregation propensities to globular proteins, and can be distinguished from unfoldable IDPs based on analysis of these sequence properties. While amino acid composition seems to be a major determinant of aggregation and secondary structure propensities, sequence randomization does not result in dramatic changes to these properties, but for both IDPs and globular proteins seems to fine-tune the tradeoff between folding and aggregation.

scholarly journals Analysis of Heterodimeric “Mutual Synergistic Folding”-Complexes

2019 ◽  
Vol 20 (20) ◽  
pp. 5136 ◽  
Author(s):  
Mentes ◽  
Magyar ◽  
Fichó ◽  
Simon
Keyword(s):  
Amino Acid ◽  
Amino Acid Composition ◽  
Acid Composition ◽  
Intrinsically Disordered Proteins ◽  
Driving Forces ◽  
Disordered Proteins ◽  
Subunit Interactions ◽  
Amino Acid Compositions ◽  
Intrinsically Disordered ◽  
Β Sheet

Several intrinsically disordered proteins (IDPs) are capable to adopt stable structures without interacting with a folded partner. When the folding of all interacting partners happens at the same time, coupled with the interaction in a synergistic manner, the process is called Mutual Synergistic Folding (MSF). These complexes represent a discrete subset of IDPs. Recently, we collected information on their complexes and created the MFIB (Mutual Folding Induced by Binding) database. In a previous study, we compared homodimeric MSF complexes with homodimeric and monomeric globular proteins with similar amino acid sequence lengths. We concluded that MSF homodimers, compared to globular homodimeric proteins, have a greater solvent accessible main-chain surface area on the contact surface of the subunits, which becomes buried during dimerization. The main driving force of the folding is the mutual shielding of the water-accessible backbones, but the formation of further intermolecular interactions can also be relevant. In this paper, we will report analyses of heterodimeric MSF complexes. Our results indicate that the amino acid composition of the heterodimeric MSF monomer subunits slightly diverges from globular monomer proteins, while after dimerization, the amino acid composition of the overall MSF complexes becomes more similar to overall amino acid compositions of globular complexes. We found that inter-subunit interactions are strengthened, and additionally to the shielding of the solvent accessible backbone, other factors might play an important role in the stabilization of the heterodimeric structures, likewise energy gain resulting from the interaction of the two subunits with different amino acid compositions. We suggest that the shielding of the β-sheet backbones and the formation of a buried structural core along with the general strengthening of inter-subunit interactions together could be the driving forces of MSF protein structural ordering upon dimerization.

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