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PreprintCited by 1Eosinophilic EsophagitisProtein Structure and DynamicsAsthma and respiratory diseases

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Bioinformatics Study on Site-Specific Variations of Eotaxin-3, a Key Chemokine in Eosinophilic Esophagitis (EoE)

Open access
Giordano, Deborah, D’Acierno, Antonio, Marabotti, Anna, Iovino, Paola, Iacomino, Giuseppe, Facchiano, Angelo·2024·Genes
DOI 10.20944/preprints202407.0870.v1PMC PMC11354214

Preprint — published as 10.3390/genes15081073 · Paper page

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Abstract

Eotaxin-3 is a key chemokine with a relevant role in eosinophilic esophagitis, a rare chronic immune/antigen-mediated inflammatory disorder. Eotaxin-3 is a potent activator of eosinophil emergence and migration, which may lead to allergic airway inflammation. We investigated by bioinformatics tools the protein structure and the possible effects of the known variations reported in public databases. Following a procedure already established, we created a 3D model of the whole protein and modelled the structure of 105 protein variants due to known point mutations. The effects of the amino acid substitution at the level of impact on protein structure, stability, and possibly function, were detected by the bioinformatics procedure and described in detail. A web application was implemented to browse the results of the analysis and visualize the 3D models, with the opportunity of downloading the models and analyze by the own software. Among 105 amino acid substitutions investigated, the study evidenced in 44 cases at least one change in any of the investigated structural parameters. Other 6 variations are also relevant, although a structural effect is not detected by our analysis, because they substituted amino acids highly conserved, which suggests a possible function role. All these variations should be the object of particular attention, as they may induce loss of functionality in the protein.

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Figures

Figure 1 3D model of eotaxin-3 in the pre-cleaved form. The image shows the backbone of the complete sequence, represented as a ribbon. The N-terminal signal peptide (yellow) is followed by the region with an N-loop (green), a central β-sheet whose β-strands (cyan) are connected by three turns (30s, 40s, 50s loop), and a C-terminal α-helix (red). Two disulfide bonds occur between C33-C57 and C34-C73 (shown in stick representation). Image has been generated by Discovery Studio software.
Figure 1 3D model of eotaxin-3 in the pre-cleaved form. The image shows the backbone of the complete sequence, represented as a ribbon. The N-terminal signal peptide (yellow) is followed by the region with an N-loop (green), a central β-sheet whose β-strands (cyan) are connected by three turns (30s, 40s, 50s loop), and a C-terminal α-helix (red). Two disulfide bonds occur between C33-C57 and C34-C73 (shown in stick representation). Image has been generated by Discovery Studio software.CC BY · PubMed Central
Figure 2 Protein sequence map of the 105 variants analyzed. The plot represents a map of the number and the position of the 105 variants analyzed along the sequence. On the x-axis is reported the position of each amino-acidic residue composing eotaxin-3, and on the y-axis is the number of missense mutations that occur in that specific position; the detail about each amino-acidic substitution in its particular position is reported in the legend. Bars are colored according to residue position in the 3D model, reported in Figure 1. The missense variants annotated as having moderate impact in UniProt are highlighted with a star (*) on the bars and circled in the legend.
Figure 2 Protein sequence map of the 105 variants analyzed. The plot represents a map of the number and the position of the 105 variants analyzed along the sequence. On the x-axis is reported the position of each amino-acidic residue composing eotaxin-3, and on the y-axis is the number of missense mutations that occur in that specific position; the detail about each amino-acidic substitution in its particular position is reported in the legend. Bars are colored according to residue position in the 3D model, reported in Figure 1. The missense variants annotated as having moderate impact in UniProt are highlighted with a star (*) on the bars and circled in the legend.CC BY · PubMed Central
Figure 3 Detail of the interactions formed by the wild-type residue Lys78 (A) and the mutated residue Glu78 (B). Green dotted lines correspond to H-bond interactions, violet lines to the peptide bonds of the protein backbone, and the red dotted lines to the salt bridge, while residues shown as red arcs are involved in hydrophobic interactions. Images are generated by Ligplus v.2.2 software.
Figure 3 Detail of the interactions formed by the wild-type residue Lys78 (A) and the mutated residue Glu78 (B). Green dotted lines correspond to H-bond interactions, violet lines to the peptide bonds of the protein backbone, and the red dotted lines to the salt bridge, while residues shown as red arcs are involved in hydrophobic interactions. Images are generated by Ligplus v.2.2 software.CC BY · PubMed Central
Figure 4 Structural position in the eotaxin-3 model of wild-type residues affected by mutations predicted as destabilizing and visualization of their mutations. Affected residues are shown as magenta ball and stick models. In overlap, the mutated residues are represented by sticks colored as reported in the graphical legend. The disulfide bonds are highlighted in cyan sticks. The image has been generated by Discovery Studio software.
Figure 4 Structural position in the eotaxin-3 model of wild-type residues affected by mutations predicted as destabilizing and visualization of their mutations. Affected residues are shown as magenta ball and stick models. In overlap, the mutated residues are represented by sticks colored as reported in the graphical legend. The disulfide bonds are highlighted in cyan sticks. The image has been generated by Discovery Studio software.CC BY · PubMed Central
Figure 5 Details of the intra-chain interactions formed by Trp80 (A) or by its substituents, i.e., Gly80 (B), Ser80 (C), Asp80 (D), Leu80, (E). Residue 80 is always represented in magenta sticks, while the residues interacting with W80 in the wild-type are shown in blue sticks. Residues interacting with residue 80 are labeled. Hydrophobic interactions are shown as purple dotted lines, while H-bond interactions are visible as green dotted lines. Protein is represented in a line ribbon and colored by secondary structure. Image has been generated by Discovery Studio software.
Figure 5 Details of the intra-chain interactions formed by Trp80 (A) or by its substituents, i.e., Gly80 (B), Ser80 (C), Asp80 (D), Leu80, (E). Residue 80 is always represented in magenta sticks, while the residues interacting with W80 in the wild-type are shown in blue sticks. Residues interacting with residue 80 are labeled. Hydrophobic interactions are shown as purple dotted lines, while H-bond interactions are visible as green dotted lines. Protein is represented in a line ribbon and colored by secondary structure. Image has been generated by Discovery Studio software.CC BY · PubMed Central

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Metadata

Authors
Giordano, D., D’Acierno, A., Marabotti, A., Iovino, P., Iacomino, G., & Facchiano, A.
Affiliations
  • Institute of Food Science (IT)
  • University of Salerno (IT)
Corresponding author
Iacomino, Giuseppe
ORCID
Venue
Genes
Publisher
MDPI AG
Published
2024-07-10
Volume
15
Issue
8
Pages
1073-1073
ISSN
2073-4425 (ISSN-L)
DOI
10.20944/preprints202407.0870.v1
PMC
PMC11354214
OpenAlex
W4401584344
Cited by
1
References
1
Citations by year
2026: 1
FWCI
0.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Genes (publishedVersion, cc-by)
  • Preprints.org (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Banca d'Italia
Topics
  • Health Sciences › Medicine › Gastroenterology › Eosinophilic Esophagitis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Asthma and respiratory diseases
Keywords
eotaxin-3, eosinophilic esophagitis, chemokines, point mutations, protein variants, protein structure, protein structure modeling, protein stability, amino acid substitutions, web application, eosinophil migration
MeSH terms
Chemokine CCL26, Humans, Models, Molecular, Computational Biology, Amino Acid Substitution, Eosinophilic Esophagitis

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CoChat. (2026). Citation check: Bioinformatics Study on Site-Specific Variations of Eotaxin-3, a Key Chemokine in Eosinophilic Esophagitis (EoE). https://app.cochat.ai/papers/10.20944/preprints202407.0870.v1
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Giordano, D., D’Acierno, A., Marabotti, A., Iovino, P., Iacomino, G., & Facchiano, A. (2024). Bioinformatics Study on Site-Specific Variations of Eotaxin-3, a Key Chemokine in Eosinophilic Esophagitis (EoE). Genes. https://doi.org/10.20944/preprints202407.0870.v1

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