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.

SolupHred: a server to predict the pH-dependent aggregation of intrinsically disordered proteins

2020 ◽  
Author(s):  
Carlos Pintado ◽  
Jaime Santos ◽  
Valentín Iglesias ◽  
Salvador Ventura
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Supplementary Information ◽  
Supplementary Data ◽  
Solution Ph ◽  
Predictive Tool ◽  
Web Based ◽  
Intrinsically Disordered ◽  
Dependent Protein ◽  
Ph Dependent

Abstract Summary Polypeptides are exposed to changing environmental conditions that modulate their intrinsic aggregation propensities. Intrinsically disordered proteins (IDPs) constitutively expose their aggregation determinants to the solvent, thus being especially sensitive to its fluctuations. However, solvent conditions are often disregarded in computational aggregation predictors. We recently developed a phenomenological model to predict IDPs' solubility as a function of the solution pH, which is based on the assumption that both protein lipophilicity and charge depend on this parameter. The model anticipated solubility changes in different IDPs accurately. In this application note, we present SolupHred, a web-based interface that implements the aforementioned theoretical framework into a predictive tool able to compute IDPs aggregation propensities as a function of pH. SolupHred is the first dedicated software for the prediction of pH-dependent protein aggregation. Availability and implementation The SolupHred web server is freely available for academic users at: https://ppmclab.pythonanywhere.com/SolupHred. It is platform-independent and does not require previous registration. Supplementary information Supplementary data are available at Bioinformatics online.

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.

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 Prediction of the effect of pH on the aggregation and conditional folding of intrinsically disordered proteins with SolupHred and DispHred.

2021 ◽  
Author(s):  
Valentin Iglesias ◽  
Carlos Pintado-Grima ◽  
Jaime Santos ◽  
Marc Fornt ◽  
Salvador Ventura
Keyword(s):  
Conformational Changes ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Net Charge ◽  
Software Applications ◽  
Intrinsically Disordered ◽  
Binding Partners ◽  
Dissolved Ions ◽  
Ph Dependent ◽  
User Friendly

Proteins microenvironments modulate their structures. Binding partners, organic molecules, or dissolved ions can alter the protein's compaction, inducing aggregation or order-disorder conformational transitions. Surprisingly, bioinformatic platforms often disregard the protein context in their modeling. In recent work, we proposed that modeling how pH affects protein net charge and hydrophobicity might allow us to forecast pH-dependent aggregation and conditional disorder in intrinsically disordered proteins (IDPs). As these approaches showed remarkable success in recapitulating the available bibliographical data, we made these prediction methods available for the scientific community as two user-friendly web servers. SolupHred is the first dedicated software to predict pH-dependent aggregation, and DispHred is the first pH-dependent predictor of protein disorder. Here we dissect the features of these two software applications to train and assist scientists in studying pH-dependent conformational changes in IDPs.

scholarly journals Liquid-Liquid Phase Separation is Driven by Large-Scale Conformational Unwinding and Fluctuations of Intrinsically Disordered Protein Molecules

2019 ◽  
Author(s):  
Anupa Majumdar ◽  
Priyanka Dogra ◽  
Shiny Maity ◽  
Samrat Mukhopadhyay
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Large Scale ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Liquid Phase Separation ◽  
Disordered Proteins ◽  
Fluorescence Depolarization ◽  
Intrinsically Disordered ◽  
Liquid Liquid Phase Separation

ABSTRACTLiquid-liquid phase separation occurs via a multitude of transient, non-covalent, intermolecular interactions resulting in phase transition of intrinsically disordered proteins/regions (IDPs/IDRs) and other biopolymers into mesoscopic, dynamic, non-stoichiometric, supramolecular condensates. IDPs resemble associative polymers possessing stereospecific “stickers” and flexible “spacers” that govern the transient chain-chain interactions and fluidity in phase-separated liquid droplets. However, the fundamental molecular origin of phase separation remains elusive. Here we present a unique case to demonstrate that unusual conformational expansion events coupled with solvation and fluctuations drive phase separation of tau, an IDP associated with Alzheimer’s disease. Using intramolecular excimer emission as a powerful proximity readout, we show the unraveling of polypeptide chains within the protein-rich interior environment that can promote critical interchain contacts. Using highly-sensitive picosecond time-resolved fluorescence depolarization measurements, we directly capture rapid large-amplitude torsional fluctuations in the extended chains that can control the relay of making-and-breaking of noncovalent intermolecular contacts maintaining the internal fluidity. Our observations, together with the existing polymer theories, suggest that such an orchestra of concerted molecular shapeshifting events involving chain expansion, solvation, and fluctuations can provide additional favorable free energies to overcome the entropy of mixing term during phase separation. The interplay of these key molecular parameters can also be of prime importance in modulating the mesoscale material property of liquid-like condensates and their maturation of into pathological gel-like and solid-like aggregates.

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.

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