scholarly journals Genomic Analysis of Intrinsically Disordered Proteins in the Genus Camelus

2020 ◽  
Vol 21 (11) ◽  
pp. 4010
Author(s):  
Manal A. Alshehri ◽  
Manee M. Manee ◽  
Mohamed B. Al-Fageeh ◽  
Badr M. Al-Shomrani
Keyword(s):  
North Africa ◽  
Protein Function ◽  
Large Scale ◽  
Intrinsically Disordered Proteins ◽  
State Of The Art ◽  
Homo Sapiens ◽  
Genomic Analysis ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Multiple State

Intrinsically disordered proteins/regions (IDPs/IDRs) fail to fold completely into 3D structures, but have major roles in determining protein function. While natively disordered proteins/regions have been found to fulfill a wide variety of primary cellular roles, the functions of many disordered proteins in numerous species remain to be uncovered. Here, we perform the first large-scale study of IDPs/IDRs in the genus Camelus, one of the most important mammalians in Asia and North Africa, in order to explore the biological roles of these proteins. The study includes the prediction of disordered proteins/regions in Camelus species and in humans using multiple state-of-the-art prediction tools. Additionally, we provide a comparative analysis of Camelus and Homo sapiens IDPs/IDRs for the sake of highlighting the distinctive use of disorder in each genus. Our findings indicate that the human proteome is more disordered than the Camelus proteome. Gene Ontology analysis also revealed that Camelus IDPs are enriched in glutathione catabolism and lactose biosynthesis.

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 Co-Evolution of Intrinsically Disordered Proteins with Folded Partners Witnessed by Evolutionary Couplings

2018 ◽  
Vol 19 (11) ◽  
pp. 3315 ◽  
Author(s):  
Rita Pancsa ◽  
Fruzsina Zsolyomi ◽  
Peter Tompa
Keyword(s):  
Large Scale ◽  
Intrinsically Disordered Proteins ◽  
Protein Structures ◽  
Disordered Proteins ◽  
Cellular Interaction ◽  
Structural Constraints ◽  
Protein Residues ◽  
Intrinsically Disordered ◽  
Evolutionary Changes ◽  
Folded Proteins

Although improved strategies for the detection and analysis of evolutionary couplings (ECs) between protein residues already enable the prediction of protein structures and interactions, they are mostly restricted to conserved and well-folded proteins. Whereas intrinsically disordered proteins (IDPs) are central to cellular interaction networks, due to the lack of strict structural constraints, they undergo faster evolutionary changes than folded domains. This makes the reliable identification and alignment of IDP homologs difficult, which led to IDPs being omitted in most large-scale residue co-variation analyses. By preforming a dedicated analysis of phylogenetically widespread bacterial IDP–partner interactions, here we demonstrate that partner binding imposes constraints on IDP sequences that manifest in detectable interprotein ECs. These ECs were not detected for interactions mediated by short motifs, rather for those with larger IDP–partner interfaces. Most identified coupled residue pairs reside close (<10 Å) to each other on the interface, with a third of them forming multiple direct atomic contacts. EC-carrying interfaces of IDPs are enriched in negatively charged residues, and the EC residues of both IDPs and partners preferentially reside in helices. Our analysis brings hope that IDP–partner interactions difficult to study could soon be successfully dissected through residue co-variation analysis.

scholarly journals DispHred: A Server to Predict pH-Dependent Order–Disorder Transitions in Intrinsically Disordered Proteins

2020 ◽  
Vol 21 (16) ◽  
pp. 5814 ◽  
Author(s):  
Jaime Santos ◽  
Valentín Iglesias ◽  
Carlos Pintado ◽  
Juan Santos-Suárez ◽  
Salvador Ventura
Keyword(s):  
Intrinsically Disordered Proteins ◽  
State Of The Art ◽  
Disordered Proteins ◽  
Protein Disorder ◽  
Net Charge ◽  
Intrinsically Disordered ◽  
Linear Boundary Condition ◽  
Natively Unfolded ◽  
Ph Dependent ◽  
Very High

The natively unfolded nature of intrinsically disordered proteins (IDPs) relies on several physicochemical principles, of which the balance between a low sequence hydrophobicity and a high net charge appears to be critical. Under this premise, it is well-known that disordered proteins populate a defined region of the charge–hydropathy (C–H) space and that a linear boundary condition is sufficient to distinguish between folded and disordered proteins, an approach widely applied for the prediction of protein disorder. Nevertheless, it is evident that the C–H relation of a protein is not unalterable but can be modulated by factors extrinsic to its sequence. Here, we applied a C–H-based analysis to develop a computational approach that evaluates sequence disorder as a function of pH, assuming that both protein net charge and hydrophobicity are dependent on pH solution. On that basis, we developed DispHred, the first pH-dependent predictor of protein disorder. Despite its simplicity, DispHred displays very high accuracy in identifying pH-induced order/disorder protein transitions. DispHred might be useful for diverse applications, from the analysis of conditionally disordered segments to the synthetic design of disorder tags for biotechnological applications. Importantly, since many disorder predictors use hydrophobicity as an input, the here developed framework can be implemented in other state-of-the-art algorithms.

scholarly journals Disorder Atlas: web-based software for the proteome-based interpretation of intrinsic disorder predictions

2016 ◽  
Author(s):  
Michael Vincent ◽  
Santiago Schnell
Keyword(s):  
Large Scale ◽  
Intrinsically Disordered Proteins ◽  
Three Dimensional ◽  
Intrinsic Disorder ◽  
Query Protein ◽  
Disordered Proteins ◽  
Dimensional Structure ◽  
Web Based ◽  
Intrinsically Disordered ◽  
Eukaryotic Proteomes

AbstractIntrinsically disordered proteins lack a stable three-dimensional structure under physiological conditions. While this property has gained considerable interest within the past two decades, disorder poses substantial challenges to experimental characterization efforts. In effect, numerous computational tools have been developed to predict disorder from primary sequences, however, interpreting the output of these algorithms remains a challenge. To begin to bridge this gap, we present Disorder Atlas, web-based software that facilitates the interpretation of intrinsic disorder predictions using proteome-based descriptive statistics. This service is also equipped to facilitate large-scale systematic exploratory searches for proteins encompassing disorder features of interest, and further allows users to browse the prevalence of multiple disorder features at the proteome level. As a result, Disorder Atlas provides a user-friendly tool that places algorithm-generated disorder predictions in the context of the proteome, thereby providing an instrument to compare the results of a query protein against predictions made for an entire population. Disorder Atlas currently supports ten eukaryotic proteomes and is freely available for non-commercial users at http://www.disorderatlas.org.

scholarly journals New technologies to analyse protein function: an intrinsic disorder perspective

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 101 ◽  
Author(s):  
Vladimir N. Uversky
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Proteins ◽  
New Technologies ◽  
Intrinsically Disordered Protein ◽  
Intrinsic Disorder ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Protein Functions ◽  
Require Structure

Functions of intrinsically disordered proteins do not require structure. Such structure-independent functionality has melted away the classic rigid “lock and key” representation of structure–function relationships in proteins, opening a new page in protein science, where molten keys operate on melted locks and where conformational flexibility and intrinsic disorder, structural plasticity and extreme malleability, multifunctionality and binding promiscuity represent a new-fangled reality. Analysis and understanding of this new reality require novel tools, and some of the techniques elaborated for the examination of intrinsically disordered protein functions are outlined in this review.

scholarly journals pH-Dependent Aggregation in Intrinsically Disordered Proteins Is Determined by Charge and Lipophilicity

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 145 ◽  
Author(s):  
Jaime Santos ◽  
Valentín Iglesias ◽  
Juan Santos-Suárez ◽  
Marco Mangiagalli ◽  
Stefania Brocca ◽  
...  
Keyword(s):  
Large Scale ◽  
Intrinsically Disordered Proteins ◽  
Phenomenological Approach ◽  
Premature Aging ◽  
Disordered Proteins ◽  
Solution Ph ◽  
Intrinsically Disordered ◽  
Large Scale Analysis ◽  
Human Disorders ◽  
Ph Dependent

Protein aggregation is associated with an increasing number of human disorders and premature aging. Moreover, it is a central concern in the manufacturing of recombinant proteins for biotechnological and therapeutic applications. Nevertheless, the unique architecture of protein aggregates is also exploited by nature for functional purposes, from bacteria to humans. The relevance of this process in health and disease has boosted the interest in understanding and controlling aggregation, with the concomitant development of a myriad of algorithms aimed to predict aggregation propensities. However, most of these programs are blind to the protein environment and, in particular, to the influence of the pH. Here, we developed an empirical equation to model the pH-dependent aggregation of intrinsically disordered proteins (IDPs) based on the assumption that both the global protein charge and lipophilicity depend on the solution pH. Upon its parametrization with a model IDP, this simple phenomenological approach showed unprecedented accuracy in predicting the dependence of the aggregation of both pathogenic and functional amyloidogenic IDPs on the pH. The algorithm might be useful for diverse applications, from large-scale analysis of IDPs aggregation properties to the design of novel reversible nanofibrillar materials.

scholarly journals Salient Features of Monomeric Alpha-Synuclein Revealed by NMR Spectroscopy

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 428
Author(s):  
Do-Hyoung Kim ◽  
Jongchan Lee ◽  
K. Mok ◽  
Jung Lee ◽  
Kyou-Hoon Han
Keyword(s):  
Structural Biology ◽  
Protein Function ◽  
Intrinsically Disordered Proteins ◽  
Alpha Synuclein ◽  
Disordered Proteins ◽  
Strongly Correlated ◽  
Proper Understanding ◽  
Intrinsically Disordered ◽  
Structural Details ◽  
The One

Elucidating the structural details of proteins is highly valuable and important for the proper understanding of protein function. In the case of intrinsically disordered proteins (IDPs), however, obtaining the structural details is quite challenging, as the traditional structural biology tools have only limited use. Nuclear magnetic resonance (NMR) is a unique experimental tool that provides ensemble conformations of IDPs at atomic resolution, and when studying IDPs, a slightly different experimental strategy needs to be employed than the one used for globular proteins. We address this point by reviewing many NMR investigations carried out on the α-synuclein protein, the aggregation of which is strongly correlated with Parkinson’s disease.

Functions of short lifetime biological structures at large: the case of intrinsically disordered proteins

2018 ◽  
Author(s):  
Vladimir N Uversky
Keyword(s):  
Biological Networks ◽  
Protein Function ◽  
Intrinsically Disordered Proteins ◽  
Protein Molecule ◽  
Biologically Active ◽  
Disordered Proteins ◽  
Substantial Part ◽  
Binding Modes ◽  
Intrinsically Disordered ◽  
Short Lifetime

Abstract Although for more than a century a protein function was intimately associated with the presence of unique structure in a protein molecule, recent years witnessed a skyrocket rise of the appreciation of protein intrinsic disorder concept that emphasizes the importance of the biologically active proteins without ordered structures. In different proteins, the depth and breadth of disorder penetrance are different, generating an amusing spatiotemporal heterogeneity of intrinsically disordered proteins (IDPs) and intrinsically disordered protein region regions (IDPRs), which are typically described as highly dynamic ensembles of rapidly interconverting conformations (or a multitude of short lifetime structures). IDPs/IDPRs constitute a substantial part of protein kingdom and have unique functions complementary to functional repertoires of ordered proteins. They are recognized as interaction specialists and global controllers that play crucial roles in regulation of functions of their binding partners and in controlling large biological networks. IDPs/IDPRs are characterized by immense binding promiscuity and are able to use a broad spectrum of binding modes, often resulting in the formation of short lifetime complexes. In their turn, functions of IDPs and IDPRs are controlled by various means, such as numerous posttranslational modifications and alternative splicing. Some of the functions of IDPs/IDPRs are briefly considered in this review to shed some light on the biological roles of short-lived structures at large.

Large-Scale Identification of Intrinsically Disordered Proteins

2010 ◽  
pp. 671-693
Author(s):  
Vladimir N. Uversky ◽  
Marc S. Cortese ◽  
Peter Tompa ◽  
Veronika Csizmok ◽  
A. Keith Dunker
Keyword(s):  
Large Scale ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered

scholarly journals Designing heterotropically activated allosteric conformational switches using supercharging

2020 ◽  
Vol 117 (10) ◽  
pp. 5291-5297 ◽  
Author(s):  
Peter J. Schnatz ◽  
Joseph M. Brisendine ◽  
Craig C. Laing ◽  
Bernard H. Everson ◽  
Cooper A. French ◽  
...  
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Proteins ◽  
Control Mechanism ◽  
Divalent Cations ◽  
High Surface ◽  
Model Systems ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Induced Folding ◽  
Low Concentrations

Heterotropic allosteric activation of protein function, in which binding of one ligand thermodynamically activates the binding of another, different ligand or substrate, is a fundamental control mechanism in metabolism and as such has been a long-aspired capability in protein design. Here we show that greatly increasing the magnitude of a protein’s net charge using surface supercharging transforms that protein into an allosteric ligand- and counterion-gated conformational molecular switch. To demonstrate this we first modified the designed helical bundle hemoprotein H4, creating a highly charged protein which both unfolds reversibly at low ionic strength and undergoes the ligand-induced folding transition commonly observed in signal transduction by intrinsically disordered proteins in biology. As a result of the high surface-charge density, ligand binding to this protein is allosterically activated up to 1,300-fold by low concentrations of divalent cations and the polyamine spermine. To extend this process further using a natural protein, we similarly modified Escherichia coli cytochrome b562 and the resulting protein behaves in a like manner. These simple model systems not only establish a set of general engineering principles which can be used to convert natural and designed soluble proteins into allosteric molecular switches useful in biodesign, sensing, and synthetic biology, the behavior we have demonstrated––functional activation of supercharged intrinsically disordered proteins by low concentrations of multivalent ions––may be a control mechanism utilized by Nature which has yet to be appreciated.

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