Computational Protein Phenotype Characterization of IL10RA Mutations Causative to Early Onset Inflammatory Bowel Disease (IBD)

Abstract

The deleterious amino acid substitution mutations in IL-10 receptor alpha gene are most frequently reported in several autoimmune diseases including early onset-inflammatory bowel disease (IBD). Despite the important role of IL-10 RA in maintaining immune homeostasis, the specific structural and functional implications of these mutations on protein phenotype, stability, ligand binding and post translational characteristics is not well explored. Therefore, this study performed the multidimensional computational analysis of IL10RA missense variations causative to pediatric or early onset inflammatory bowel disease (<5 years of age). Our computational algorithmic screening identified the deleterious nature of p. W45G, p. Y57C, p. W69G, p.T84I, p.Y91C, p.R101W, p.R117C, and p.R117H, IBD causative IL10-RA mutations. The sensitivity and specificity analysis of different computational methods showed that CADD outperform SIFT, PolyPhen 2.0, FATHMM, LRT, MetaLR, MetaSVM, PROVEAN and Condel in predicting the pathogenicity of IL10RA mutations. Our three-dimensional protein modeling assays showed that the point mutations cause major drifts in the structural plasticity of IL10 RA molecule and negatively influence its stability. Findings from molecular docking analysis have shown that these point mutations decrease the binding affinity of IL10RA toward IL10 and may likely to disturb the IL10 signaling pathway. This study provides an easy frame work for phenotypic characterization of mutant IL10RA molecule in terms of structure, flexibility and stability aspects. Our approach may also add a new dimension to conventional functional biology assays in quickly studying IL10 RA mutations and also for designing and developing inhibitors for mutant IL10RA molecule.

An Integrative Bioinformatics Analysis of the Potential Mechanisms Involved in Propofol Affecting Hippocampal Neuronal Cells

“…CD86 may act as a key regulator of the immune response to disease through a T cell-mediated mechanism, and thus it has great potential to become a new target for immunotherapy [ 15 ]. IL10RA consists mainly of a heterotetramer of the anti-inflammatory cytokine IL10 receptor and belongs to class II cytokines [ 16 , 17 ]. IL10RA is usually located as a cell surface receptor upstream of STAT3, and it can bind IL-10 together with IL10RB to mediate downstream signaling via STAT3 [ 18 ].…”

Bioinformatics-Based Study to Investigate Potential Differentially Expressed Genes and miRNAs in Hashimoto’s Thyroiditis

“…IL10 was a crucial anti-inflammatory cytokine that inhibits the pro-inflammatory responses of innate and adaptive immune cells [22]. Some reports indicated that IL10RA was related to early onset-inflammatory bowel disease [23], anaplastic large cell lymphoma [24], colorectal cancer [25]. Chemokine (C-C motif) ligand 2 (CCL2) was also known as monocyte chemotactic protein 1 (MCP1) and small inducible cytokine A2.…”

Computational Molecular Phenotypic Analysis of PTPN22 (W620R), IL6R (D358A), and TYK2 (P1104A) Gene Mutations of Rheumatoid Arthritis

“…These findings underline that nucleotide variant prediction methods are not always sensitive in predicting the pathogenic potential of clinically significant variants. This could be due to the differences in datasets used in training these variant prediction programs ( Al-Abbasi et al, 2018 ). We have therefore further investigated the impact of RA mutations on structural features of proteins.…”