Comparative Analysis of Structural Features in SLiMs from Eukaryotes, Bacteria, and Viruses with Importance for Host-Pathogen Interactions
<p>The SLiM dataset composition by taxonomy and functionality. The percentage of SLiMs per taxonomic group and taxonomic subgroup; eukaryotes and its subgroups (grey), viruses and its subgroups (blue), and bacteria (green) based on all SLiMs (<b>A</b>). The percentage of SLiMs is colored by functional type in each taxonomic group (<b>B</b>). For further information, see <a href="#app1-pathogens-11-00583" class="html-app">Table S1</a>.</p> "> Figure 2
<p>Predicted properties per instance across taxonomic groups. The predicted percentage per instance; IUPRED2A long disorder based on 0.5 cutoff (<b>A</b>) and 0.4 cutoff (<b>B</b>), IUPRED2A short disorder based on 0.5 cutoff (<b>C</b>) and 0.4 cutoff (<b>D</b>), NetSurfP 2.0 accessibility based on 0.25 cutoff (<b>E</b>), and NetSurfP 2.0 prediction of coil based on three state analysis (<b>F</b>). For further information, see <a href="#app1-pathogens-11-00583" class="html-app">Table S1</a>.</p> "> Figure 3
<p>Distribution of MIDS values. Boxplots for the distribution of long IUPRED2A MIDS of all SLiMs per motif type colored as shown by legend (<b>A</b>). Boxplots for long IUPRED2A MIDS distribution of all SLiMs in each taxonomic group (bacteria (green), viruses (blue), eukaryotes (grey)) classified based on their ELM type (<b>B</b>). Boxplots for the distribution of long IUPRED2A MIDS of all SLiMs per motif type colored as shown by legend (<b>C</b>). Boxplots for long IUPRED2A MIDS distribution of all SLiMs in each taxonomic group, colored as in (<b>B</b>), classified based on their ELM type (<b>D</b>). Hypothesis testing with Mann–Whitney test with simple Bonferroni correction was performed and significant adjusted <span class="html-italic">p</span>-values in (<b>A</b>,<b>B</b>) are shown as brackets between groups (No asterisk for adjusted <span class="html-italic">p</span>-values between 0.05 and <0.01, * for adjusted <span class="html-italic">p</span>-value ≤ 0.01, ** for ≤1 × 10<sup>−3</sup>, and *** for ≤1 × 10<sup>−4</sup>). The sample size per each tested group and adjusted <span class="html-italic">p</span>-values can be found in <a href="#app1-pathogens-11-00583" class="html-app">Table S1</a>. The percentage of SLiMs by long IUPED2A MIDS range in different taxonomic groups colored by ELM type (<b>E</b>–<b>G</b>). The percentage of SLiMs by short IUPED2A MIDS range in different taxonomic groups colored by ELM type (<b>H</b>–<b>J</b>), colored as in (<b>A</b>). For more information, see <a href="#app1-pathogens-11-00583" class="html-app">Tables S1 and S2</a>.</p> "> Figure 4
<p><b>Distribution of MCCS values.</b> Boxplots for the distribution of MCCS of all SLiMs per motif type colored as shown by legend (<b>A</b>). Boxplots for MCCS distribution of all SLiMs in each taxonomic group (bacteria in green, viruses in blue, and eukaryotes in grey) classified based on their ELM type (<b>B</b>). Hypothesis testing with Mann–Whitney test with simple Bonferroni correction was performed and significant adjusted <span class="html-italic">p</span>-values in (<b>A</b>,<b>B</b>) are shown as brackets between groups (No asterisk for adjusted <span class="html-italic">p</span>-values between 0.05 to <0.01, * for adjusted <span class="html-italic">p</span>-value ≤ 0.01, and *** for ≤1 × 10<sup>−4</sup>). The sample size per each tested group and adjusted <span class="html-italic">p</span>-values can be found in <a href="#app1-pathogens-11-00583" class="html-app">Table S1</a>. The percentage of SLiMs by MCCS range in different taxonomic groups colored by ELM type (<b>C</b>–<b>E</b>) colored as in (<b>A</b>). For more information, see <a href="#app1-pathogens-11-00583" class="html-app">Tables S1 and S2</a>.</p> "> Figure 5
<p>Disorder and coil confidence profiles of proteins containing SLiMs and the density curve of MIDS and MCCS of SLiMs per taxonomic group. The flanking regions of 100 residues around SLiMs using long IUPRED2A disorder score per taxonomic group and the 95% confidence interval of the mean (<b>A</b>). SLiMs long IUPRED2A MIDS density distribution plot of the SLiMs per taxonomic group (<b>B</b>). The flanking regions of 100 residues around SLiMs using short IUPRED2A disorder score per taxonomic group and the 95% confidence interval of the mean (<b>C</b>). SLiMs short IUPRED2A MIDS density distribution plot of the SLiMs per taxonomic group (<b>D</b>). The flanking regions of 100 residues around SLiMs coil confidence score per taxonomic group and the 95% confidence interval of the mean (<b>E</b>). SLiMs MCCS density distribution plot of the SLiMs per taxonomic group (<b>F</b>). For further information, see <a href="#app1-pathogens-11-00583" class="html-app">Table S3</a>.</p> "> Figure 6
<p>Scatter plot for the MIDS and MCCS means of the shared SLiMs between different groups. Long disorder MIDS means scatter plot and Spearman correlation with the <span class="html-italic">p</span>-value for shared SLiMs between eukaryotes vs. bacteria (<b>A</b>) and eukaryotes vs. viruses (<b>B</b>). Short disorder MIDS means scatter plot and Spearman correlation with the <span class="html-italic">p</span>-value for shared SLiMs between eukaryotes vs. bacteria (<b>C</b>) and eukaryotes vs. viruses (<b>D</b>). MCCS means scatter plot and Spearman correlation with the <span class="html-italic">p</span>-value for shared SLiMs between eukaryotes vs. bacteria (<b>E</b>) and eukaryotes vs. viruses (<b>F</b>). For detailed information about the number of instances, long/short mMIDS and mMCCS of all instances per motif, long/short MIDS and MCCS per instance, and the individual amino acid scores of disorder and coil confidence per instance, see <a href="#app1-pathogens-11-00583" class="html-app">Table S4</a>.</p> "> Figure 7
<p>Disorder score and coil confidence distributions in viruses and eukaryotes for the MOD_N-GLC_1 motif. Boxplots and swarm plot distribution for SLiMs long IUPRED2A MIDS (<b>A</b>), short IUPRED2A MIDS (<b>B</b>), MCCS (<b>C</b>), the individual long IUPRED2A disorder scores per residue for SLiMs (<b>D</b>), the individual short IUPRED2A disorder scores per residue for SLiMs (<b>E</b>), and the individual coil confidence scores per residue for SLiMs (<b>F</b>).</p> "> Figure 8
<p>The glycosylated MOD_N-GLC_1 site in West Nile virus envelope protein. West Nile Virus envelope protein (beige) (PDB ID: 2HG0) rendered as a transparent surface. A closer view of the local helical structure of the MOD_N-GLC_1 motif (magenta). The glycosylated asparagine residue (blue) and glycan group (cyan) are shown as sticks.</p> "> Figure 9
<p>Phylogenetic tree of West Nile Virus (WNV) envelope protein illustrating the evolution of structural properties of a MOD_N-GLC_1 motif. The tree, rooted by the outgroup Yellow Fever virus (YFV)), shows WNV in green and Zika virus (ZIKV), Dengue virus 2 (DENV2), and Japanese Encephalitis Virus (JEV) that have been shown to be glycosylated in this position but that are not in the ELM database in blue. The tree is shown next to an excerpt from the multiple sequence alignment with the MOD_N-GLC_1 motif pattern highlighted in black, followed by the same alignment excerpt colored by the accessibility and secondary structure of the residues (<b>A</b>) and by disorder using both 0.5 and 0.4 cutoff values for long IUPRED2A and short IUPRED2A disorder, with the location of the WNV MOD_N-GLC_1 motif shown by the black box (<b>B</b>). For further details, see <a href="#app1-pathogens-11-00583" class="html-app">Figure S5</a>.</p> "> Figure 10
<p>Disorder score and coil confidence distributions in viruses and eukaryotes for the LIG_Rb_LxCxE_1 motif. Boxplots and swarm plot distribution for SLiMs long IUPRED2A MIDS (<b>A</b>), short IUPRED2A MIDS (<b>B</b>), MCCS (<b>C</b>), individual long IUPRED2A disorder scores per residue for SLiMs (<b>D</b>), individual short IUPRED2A disorder scores per residue for SLiMs (<b>E</b>), and individual coil confidence scores per residue for SLiMs (<b>F</b>).</p> "> Figure 11
<p>LIG_Rb_LxCxE_1 motif segment from Simian V40 (large T antigen protein) and human papillomaviruses (E7) proteins in a bound state with retinoblastoma protein. The complete structures from PDB ID: 1GH6 and PDB ID: 1GUX are aligned, and a closer view of the LxCxE binding site is shown. Retinoblastoma protein (beige and cyan) is rendered as a cartoon. Large T antigen protein is shown as a cartoon (dark pink). The E7 of the human papillomavirus motif segment is shown as ribbon (brown). The LxCxE motif in both proteins is shown as sticks. The structural alignment of the entire two structures was performed in PyMOL (PyMOL Molecular Graphics System, Version 4.6).</p> ">
Abstract
:1. Introduction
2. Results and Discussion
2.1. The Majority of Instances in the ELM Database Bind Ligands and Are from Human
2.2. Accessibility and Lack of Secondary Structure Influence SLiM Functionality More than Disorder
2.3. SLiMs from Viruses Are Less Disordered
2.4. Most SLiMs Lack Secondary Structure
2.5. Disordered or Flexible?
2.5.1. SLiMs Are Found in Flexible Regions
2.5.2. A Comparison of Viral and Bacterial Motifs with Their Corresponding Eukaryotic Motifs
2.5.3. To Fold or Not to Fold: A Tale of Two Motifs
Are MOD_N-GLC_1 Instances Indeed Predominantly Ordered in Viruses or Is This Perhaps Due to Insufficient Data?
LIG_Rb_LxCxE_1 Is Less Disordered in Viruses
3. Conclusions
4. Methods
4.1. The ELM Dataset
4.2. Sequence-Based Structural Predictions
4.2.1. Intrinsic Disorder Prediction
4.2.2. Relative Solvent Accessibility and Secondary Structure Predictions
4.3. Phylogenetic Tree Analysis
4.4. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
PPI | Protein-protein interactions |
ELM | Eukaryotic Linear Motifs |
SLiMs | Short Linear Motifs |
IDR | Intrinsically Disordered protein Region |
IDP | Intrinsically Disordered Protein |
MIDS | Mean IUPRED2A Disorder Score |
MCCS | Mean Coil Confidence Score |
mMIDS | mean MIDS |
mMCCS | mean MCCS |
LIG | Ligand binding motifs |
MOD | Post-translational modification motifs |
TRG | Targeting motifs |
DOC | Docking motifs |
CLV | Cleavage sites motifs |
DEG | Degradation motifs |
WNV | West Nile Virus |
Rb | Retinoblastoma protein |
DSSP | Dictionary of Secondary Structure of Proteins |
PDB | Protein Data Bank |
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Elkhaligy, H.; Balbin, C.A.; Siltberg-Liberles, J. Comparative Analysis of Structural Features in SLiMs from Eukaryotes, Bacteria, and Viruses with Importance for Host-Pathogen Interactions. Pathogens 2022, 11, 583. https://doi.org/10.3390/pathogens11050583
Elkhaligy H, Balbin CA, Siltberg-Liberles J. Comparative Analysis of Structural Features in SLiMs from Eukaryotes, Bacteria, and Viruses with Importance for Host-Pathogen Interactions. Pathogens. 2022; 11(5):583. https://doi.org/10.3390/pathogens11050583
Chicago/Turabian StyleElkhaligy, Heidy, Christian A. Balbin, and Jessica Siltberg-Liberles. 2022. "Comparative Analysis of Structural Features in SLiMs from Eukaryotes, Bacteria, and Viruses with Importance for Host-Pathogen Interactions" Pathogens 11, no. 5: 583. https://doi.org/10.3390/pathogens11050583
APA StyleElkhaligy, H., Balbin, C. A., & Siltberg-Liberles, J. (2022). Comparative Analysis of Structural Features in SLiMs from Eukaryotes, Bacteria, and Viruses with Importance for Host-Pathogen Interactions. Pathogens, 11(5), 583. https://doi.org/10.3390/pathogens11050583