Analyzing Protein Disorder with IUPred2A

Erdős, Gábor; Dosztányi, Zsuzsanna

doi:10.1002/cpbi.99

Cited by 292 publications

(275 citation statements)

References 27 publications

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“…1). The remaining domains of SARS-CoV-2-N are highly disordered, and contain three intrinsically disordered regions (IDRs), with one also displaying prion-like activity, according to the predictions using IUPred2 28,29 and PLAAC 30 programs (Fig. 1a).…”

Section: Resultsmentioning

confidence: 99%

Understanding the phase separation characteristics of nucleocapsid protein provides a new therapeutic opportunity against SARS-CoV-2

Zhao

Zhang

et al. 2020

Preprint

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The ongoing coronavirus disease 2019 (COVID-19) pandemic has raised an urgent need to develop effective therapeutics against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As a potential antiviral drug target, the nucleocapsid (N) protein of SARS-CoV-2 functions as a viral RNA chaperone and plays vital and multifunctional roles during the life cycle of coronavirus1-3. In this study, we discovered that the N protein of SARS-CoV-2 undergoes liquid-liquid phase separation (LLPS) both in vitro and in vivo, which is further modulated by viral RNA. In addition, we found that, the core component of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, nsp12, preferentially partitions into the N protein condensates. Moreover, we revealed that, two small molecules, i.e., CVL218 and PJ34, can be used to intervene the N protein driven phase separation and loosen the compact structures of the condensates of the N-RNA-nsp12 complex of SARS-CoV-2. The discovery of the LLPS-mediated interplay between N protein and nsp12 and the corresponding modulating compounds illuminates a feasible way to improve the accessibility of antiviral drugs (e.g., remdesivir) to their targets (e.g., nsp12/RdRp), and thus may provide useful hints for further development of effective therapeutic strategies against SARS-CoV-2.

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Section: Resultsmentioning

confidence: 99%

Understanding the phase separation characteristics of nucleocapsid protein provides a new therapeutic opportunity against SARS-CoV-2

Zhao

Zhang

et al. 2020

Preprint

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“…We categorized sequences as ‘highly structured’ (0-10% of the total protein length is unstructured), ‘moderately unstructured’ (10-30% of the protein is unstructured) and ‘highly unstructured’ (30-100% of the protein is unstructured) following the classification of Gsponer et al 34 A map of intrinsic disorder regions and binding sites within each of the reference sequence coding regions were produced using IUPred2A. 35 , 36 In addition, the Anchor2 algorithm implemented in IUPred was used to predict binding regions of viral protein based on the amino acid sequence. The algorithm is designed to identify segments in disordered regions that have the capability to gain energy by interacting with a globular partner protein.…”

Section: Methodsmentioning

confidence: 99%

New Pathways of Mutational Change in SARS-CoV-2 Proteomes Involve Regions of Intrinsic Disorder Important for Virus Replication and Release

Tomaszewski

DeVries

Dong

et al. 2020

Evol Bioinform Online

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The massive worldwide spread of the SARS-CoV-2 virus is fueling the COVID-19 pandemic. Since the first whole-genome sequence was published in January 2020, a growing database of tens of thousands of viral genomes has been constructed. This offers opportunities to study pathways of molecular change in the expanding viral population that can help identify molecular culprits of virulence and virus spread. Here we investigate the genomic accumulation of mutations at various time points of the early pandemic to identify changes in mutationally highly active genomic regions that are occurring worldwide. We used the Wuhan NC_045512.2 sequence as a reference and sampled 15 342 indexed sequences from GISAID, translating them into proteins and grouping them by month of deposition. The per-position amino acid frequencies and Shannon entropies of the coding sequences were calculated for each month, and a map of intrinsic disorder regions and binding sites was generated. The analysis revealed dominant variants, most of which were located in loop regions and on the surface of the proteins. Mutation entropy decreased between March and April of 2020 after steady increases at several sites, including the D614G mutation site of the spike (S) protein that was previously found associated with higher case fatality rates and at sites of the NSP12 polymerase and the NSP13 helicase proteins. Notable expanding mutations include R203K and G204R of the nucleocapsid (N) protein inter-domain linker region and G251V of the viroporin encoded by ORF3a between March and April. The regions spanning these mutations exhibited significant intrinsic disorder, which was enhanced and decreased by the N-protein and viroporin 3a protein mutations, respectively. These results predict an ongoing mutational shift from the spike and replication complex to other regions, especially to encoded molecules known to represent major β-interferon antagonists. The study provides valuable information for therapeutics and vaccine design, as well as insight into mutation tendencies that could facilitate preventive control.

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“…Other attempts have been made to predicts these segments from more general sequence features with some degree of success [78][79][80][81][82] . The ANCHOR/ANCHOR2 method differs from other methods, estimating the disordering binding propensity as the product of the disorder probability and the estimated amino acid pair energy gained upon binding [83][84][85][86] . For example, for p53 discussed above, ANCHOR/ANCHOR2 assigns a high probability for disordered binding to the N-terminal region (residues 20-60) and the C-terminal region (residues 380-398) 87 , which was also predicted by MoRF MPM 80,87 .…”

Section: Evaluation Of Odinpred On Four Important Examples Of Disordementioning

confidence: 99%

ODiNPred: comprehensive prediction of protein order and disorder

Dass

Mulder

Nielsen

2020

Sci Rep

162

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Structural disorder is widespread in eukaryotic proteins and is vital for their function in diverse biological processes. It is therefore highly desirable to be able to predict the degree of order and disorder from amino acid sequence. It is, however, notoriously difficult to predict the degree of local flexibility within structured domains and the presence and nuances of localized rigidity within intrinsically disordered regions. To identify such instances, we used the CheZOD database, which encompasses accurate, balanced, and continuous-valued quantification of protein (dis)order at amino acid resolution based on NMR chemical shifts. To computationally forecast the spectrum of protein disorder in the most comprehensive manner possible, we constructed the sequence-based protein order/disorder predictor ODiNPred, trained on an expanded version of CheZOD. ODiNPred applies a deep neural network comprising 157 unique sequence features to 1325 protein sequences together with the experimental NMR chemical shift data. Cross-validation for 117 protein sequences shows that ODiNPred better predicts the continuous variation in order along the protein sequence, suggesting that contemporary predictors are limited by the quality of training data. The inclusion of evolutionary features reduces the performance gap between ODiNPred and its peers, but analysis shows that it retains greater accuracy for the more challenging prediction of intermediate disorder.

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Analyzing Protein Disorder with IUPred2A

Cited by 292 publications

References 27 publications

Understanding the phase separation characteristics of nucleocapsid protein provides a new therapeutic opportunity against SARS-CoV-2

Understanding the phase separation characteristics of nucleocapsid protein provides a new therapeutic opportunity against SARS-CoV-2

New Pathways of Mutational Change in SARS-CoV-2 Proteomes Involve Regions of Intrinsic Disorder Important for Virus Replication and Release

ODiNPred: comprehensive prediction of protein order and disorder

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