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.

Structural characterization of intrinsically disordered proteins by the combined use of NMR and SAXS

2012 ◽  
Vol 40 (5) ◽  
pp. 955-962 ◽  
Author(s):  
Nathalie Sibille ◽  
Pau Bernadó
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Dynamic Models ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Main Tool ◽  
Structural Features ◽  
Disordered Proteins ◽  
Dimensional Structure ◽  
Intrinsically Disordered ◽  
Conformational Preferences

In recent years, IDPs (intrinsically disordered proteins) have emerged as pivotal actors in biology. Despite IDPs being present in all kingdoms of life, they are more abundant in eukaryotes where they are involved in the vast majority of regulation and signalling processes. The realization that, in some cases, functional states of proteins were partly or fully disordered was in contradiction to the traditional view where a well defined three-dimensional structure was required for activity. Several experimental evidences indicate, however, that structural features in IDPs such as transient secondary-structural elements and overall dimensions are crucial to their function. NMR has been the main tool to study IDP structure by probing conformational preferences at residue level. Additionally, SAXS (small-angle X-ray scattering) has the capacity to report on the three-dimensional space sampled by disordered states and therefore complements the local information provided by NMR. The present review describes how the synergy between NMR and SAXS can be exploited to obtain more detailed structural and dynamic models of IDPs in solution. These combined strategies, embedded into computational approaches, promise the elucidation of the structure–function properties of this important, but elusive, family of biomolecules.

scholarly journals Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 140
Author(s):  
Giuliana Fusco ◽  
Stefano Gianni
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Three Dimensional ◽  
Disordered Proteins ◽  
Dimensional Structure ◽  
Native State ◽  
Three Dimensional Structure ◽  
Considerable Fraction ◽  
Intrinsically Disordered ◽  
Eukaryotic Proteins

The discovery that a considerable fraction of the eukaryotic proteins lacks a well-defined three-dimensional structure in their native state has revolutionised our general understanding of proteins [...]

scholarly journals Quantitative proteome-based guidelines for intrinsic disorder characterization

2015 ◽  
Author(s):  
Michael Vincent ◽  
Mark Whidden ◽  
Santiago Schnell
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Objective Assessment ◽  
Intrinsic Disorder ◽  
Disordered Proteins ◽  
Dimensional Structure ◽  
Sequence Length ◽  
Valuable Insight ◽  
Disorder Prediction ◽  
Intrinsically Disordered ◽  
Prediction Algorithms

AbstractIntrinsically disordered proteins fail to adopt a stable three-dimensional structure under physiological conditions. It is now understood that many disordered proteins are not dysfunctional, but instead engage in numerous cellular processes, including signaling and regulation. Disorder characterization from amino acid sequence relies on computational disorder prediction algorithms. While numerous large-scale investigations of disorder have been performed using these algorithms, and have offered valuable insight regarding the prevalence of protein disorder in many organisms, critical proteome-based descriptive statistical guidelines that would enable the objective assessment of intrinsic disorder in a protein of interest remain to be established. Here we present a quantitative characterization of numerous disorder features using a rigorous non-parametric statistical approach, providing expected values and percentile cutoffs for each feature in ten eukaryotic proteomes. Our estimates utilize multiple ab initio disorder prediction algorithms grounded on physicochemical principles. Furthermore, we present novel threshold values, specific to both the prediction algorithms and the proteomes, defining the longest primary sequence length in which the significance of a continuous disordered region can be evaluated on the basis of length alone. The guidelines presented here are intended to improve the interpretation of disorder content and continuous disorder predictions from the proteomic point of view.

scholarly journals Exclusively heteronuclear NMR experiments for the investigation of intrinsically disordered proteins: focusing on proline residues

2021 ◽  
Author(s):  
Isabella C. Felli ◽  
Wolfgang Bermel ◽  
Roberta Pierattelli
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Heteronuclear Nmr ◽  
Three Dimensional ◽  
Spectroscopic Technique ◽  
Disordered Proteins ◽  
Amide Proton ◽  
Dimensional Structure ◽  
Intrinsically Disordered ◽  
Valuable Complement ◽  
Polypeptide Chains

Abstract. NMR represents a key spectroscopic technique to contribute to the emerging field of highly flexible, intrinsically disordered proteins (IDPs) or protein regions (IDRs) that lack a stable three-dimensional structure. A set of exclusively heteronuclear NMR experiments tailored for proline residues, highly abundant in IDPs/IDRs, are presented here. They provide a valuable complement to the widely used approach based on amide proton detection, filling the gap introduced by the lack of amide protons in prolines within polypeptide chains. The novel experiments have very interesting properties for the investigations of IDPs/IDRs of increasing complexity.

scholarly journals Exclusively heteronuclear NMR experiments for the investigation of intrinsically disordered proteins: focusing on proline residues

2021 ◽  
Vol 2 (1) ◽  
pp. 511-522
Author(s):  
Isabella C. Felli ◽  
Wolfgang Bermel ◽  
Roberta Pierattelli
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Heteronuclear Nmr ◽  
Three Dimensional ◽  
Spectroscopic Technique ◽  
Disordered Proteins ◽  
Amide Proton ◽  
Dimensional Structure ◽  
Intrinsically Disordered ◽  
Valuable Complement ◽  
Polypeptide Chains

Abstract. NMR represents a key spectroscopic technique that contributes to the emerging field of highly flexible, intrinsically disordered proteins (IDPs) or protein regions (IDRs) that lack a stable three-dimensional structure. A set of exclusively heteronuclear NMR experiments tailored for proline residues, highly abundant in IDPs/IDRs, are presented here. They provide a valuable complement to the widely used approach based on amide proton detection, filling the gap introduced by the lack of amide protons in proline residues within polypeptide chains. The novel experiments have very interesting properties for the investigations of IDPs/IDRs of increasing complexity.

scholarly journals Analysis of the dark proteome of Chandipura virus reveals maximum propensity for intrinsic disorder in phosphoprotein

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nishi R. Sharma ◽  
Kundlik Gadhave ◽  
Prateek Kumar ◽  
Mohammad Saif ◽  
Md. M. Khan ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Three Dimensional ◽  
Maximum Level ◽  
Intrinsic Disorder ◽  
Life Cycles ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Chandipura Virus ◽  
Dynamics Simulations ◽  
Cycle Regulation

AbstractChandipura virus (CHPV, a member of the Rhabdoviridae family) is an emerging pathogen that causes rapidly progressing influenza-like illness and acute encephalitis often leading to coma and death of the human host. Given several CHPV outbreaks in Indian sub-continent, recurring sporadic cases, neurological manifestation, and high mortality rate of this infection, CHPV is gaining global attention. The ‘dark proteome’ includes the whole proteome with special emphasis on intrinsically disordered proteins (IDP) and IDP regions (IDPR), which are proteins or protein regions that lack unique (or ordered) three-dimensional structures within the cellular milieu. These proteins/regions, however, play a number of vital roles in various biological processes, such as cell cycle regulation, control of signaling pathways, etc. and, therefore, are implicated in many human diseases. IDPs and IPPRs are also abundantly found in many viral proteins enabling their multifunctional roles in the viral life cycles and their capability to highjack various host systems. The unknown abundance of IDP and IDPR in CHPV, therefore, prompted us to analyze the dark proteome of this virus. Our analysis revealed a varying degree of disorder in all five CHPV proteins, with the maximum level of intrinsic disorder propensity being found in Phosphoprotein (P). We have also shown the flexibility of P protein using extensive molecular dynamics simulations up to 500 ns (ns). Furthermore, our analysis also showed the abundant presence of the disorder-based binding regions (also known as molecular recognition features, MoRFs) in CHPV proteins. The identification of IDPs/IDPRs in CHPV proteins suggests that their disordered regions may function as potential interacting domains and may also serve as novel targets for disorder-based drug designs.

scholarly journals Understanding the Binding Induced Folding of Intrinsically Disordered Proteins by Protein Engineering: Caveats and Pitfalls

2020 ◽  
Vol 21 (10) ◽  
pp. 3484 ◽  
Author(s):  
Francesca Malagrinò ◽  
Lorenzo Visconti ◽  
Livia Pagano ◽  
Angelo Toto ◽  
Francesca Troilo ◽  
...  
Keyword(s):  
Free Energy ◽  
Intrinsically Disordered Proteins ◽  
Three Dimensional ◽  
Globular Proteins ◽  
Disordered Proteins ◽  
Dimensional Structure ◽  
Value Analysis ◽  
Intrinsically Disordered ◽  
Induced Folding ◽  
Key Techniques

Many proteins lack a well-defined three-dimensional structure in isolation. These proteins, typically denoted as intrinsically disordered proteins (IDPs), may display a characteristic disorder-to-order transition when binding their physiological partner(s). From an experimental perspective, it is of great importance to establish the general grounds to understand how such folding processes may be explored. Here we discuss the caveats and the pitfalls arising when applying to IDPs one of the key techniques to characterize the folding of globular proteins, the Φ value analysis. This method is based on measurements of the free energy changes of transition and native states upon conservative, non-disrupting, mutations. On the basis of available data, we reinforce the validity of Φ value analysis in the study of IDPs and suggest future experiments to further validate this powerful experimental method.

scholarly journals Molecular chaperones: guardians of the proteome in normal and disease states

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 1448 ◽  
Author(s):  
Wilson Jeng ◽  
Sukyeong Lee ◽  
Nuri Sung ◽  
Jungsoon Lee ◽  
Francis T.F. Tsai
Keyword(s):  
Molecular Chaperones ◽  
Protein Unfolding ◽  
Intrinsically Disordered Proteins ◽  
Protein Quality ◽  
Three Dimensional ◽  
Forward Direction ◽  
Disordered Proteins ◽  
Dimensional Structure ◽  
Functional Protein ◽  
Intrinsically Disordered

Proteins must adopt a defined three-dimensional structure in order to gain functional activity, or must they? An ever-increasing number of intrinsically disordered proteins and amyloid-forming polypeptides challenge this dogma. While molecular chaperones and proteases are traditionally associated with protein quality control inside the cell, it is now apparent that molecular chaperones not only promote protein folding in the “forward” direction by facilitating folding and preventing misfolding and aggregation, but also facilitate protein unfolding and even disaggregation resulting in the recovery of functional protein from aggregates. Here, we review our current understanding of ATP-dependent molecular chaperones that harness the energy of ATP binding and hydrolysis to fuel their chaperone functions. An emerging theme is that most of these chaperones do not work alone, but instead function together with other chaperone systems to maintain the proteome. Hence, molecular chaperones are the major component of the proteostasis network that guards and protects the proteome from damage. Furthermore, while a decline of this network is detrimental to cell and organismal health, a controlled perturbation of the proteostasis network may offer new therapeutic avenues against human diseases.

scholarly journals Generation of the configurational ensemble of an intrinsically disordered protein from unbiased molecular dynamics simulation

2019 ◽  
Vol 116 (41) ◽  
pp. 20446-20452 ◽  
Author(s):  
Utsab R. Shrestha ◽  
Puneet Juneja ◽  
Qiu Zhang ◽  
Viswanathan Gurumoorthy ◽  
Jose M. Borreguero ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Intrinsically Disordered Proteins ◽  
Chemical Shifts ◽  
Intrinsically Disordered Protein ◽  
Physical Models ◽  
Dynamics Simulation ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Eukaryotic Proteomes ◽  
Heterogeneous Ensemble

Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes, play a major role in cell signaling, and are associated with human diseases. To understand IDP function it is critical to determine their configurational ensemble, i.e., the collection of 3-dimensional structures they adopt, and this remains an immense challenge in structural biology. Attempts to determine this ensemble computationally have been hitherto hampered by the necessity of reweighting molecular dynamics (MD) results or biasing simulation in order to match ensemble-averaged experimental observables, operations that reduce the precision of the generated model because different structural ensembles may yield the same experimental observable. Here, by employing enhanced sampling MD we reproduce the experimental small-angle neutron and X-ray scattering profiles and the NMR chemical shifts of the disordered N terminal (SH4UD) of c-Src kinase without reweighting or constraining the simulations. The unbiased simulation results reveal a weakly funneled and rugged free energy landscape of SH4UD, which gives rise to a heterogeneous ensemble of structures that cannot be described by simple polymer theory. SH4UD adopts transient helices, which are found away from known phosphorylation sites and could play a key role in the stabilization of structural regions necessary for phosphorylation. Our findings indicate that adequately sampled molecular simulations can be performed to provide accurate physical models of flexible biosystems, thus rationalizing their biological function.

scholarly journals Disorder in a two-domain neuronal Ca2+-binding protein regulates domain stability and dynamics using ligand mimicry

2020 ◽  
Author(s):  
Lasse Staby ◽  
Katherine R. Kemplen ◽  
Amelie Stein ◽  
Michael Ploug ◽  
Jane Clarke ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Three Dimensional ◽  
Life Time ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Order And Disorder ◽  
C Terminus ◽  
Close Relationship ◽  
Stability Dynamics ◽  
And Function

Abstract Understanding the interplay between sequence, structure and function of proteins has been complicated in recent years by the discovery of intrinsically disordered proteins (IDPs), which perform biological functions in the absence of a well-defined three-dimensional fold. Disordered protein sequences account for roughly 30% of the human proteome and in many proteins, disordered and ordered domains coexist. However, few studies have assessed how either feature affects the properties of the other. In this study, we examine the role of a disordered tail in the overall properties of the two-domain, calcium-sensing protein neuronal calcium sensor 1 (NCS-1). We show that loss of just six of the 190 residues at the flexible C-terminus is sufficient to severely affect stability, dynamics, and folding behavior of both ordered domains. We identify specific hydrophobic contacts mediated by the disordered tail that may be responsible for stabilizing the distal N-terminal domain. Moreover, sequence analyses indicate the presence of an LSL-motif in the tail that acts as a mimic of native ligands critical to the observed order–disorder communication. Removing the disordered tail leads to a shorter life-time of the ligand-bound complex likely originating from the observed destabilization. This close relationship between order and disorder may have important implications for how investigations into mixed systems are designed and opens up a novel avenue of drug targeting exploiting this type of behavior.

Sign in / Sign up

Export Citation Format

Share Document