Abstract
Immunogenicity of gliadin peptides in celiac disease (CD) is majorly determined by the pattern of molecular interactions with HLA-DQ and T-cell receptors (TCR). Investigation of the interactions between immune-dominant gliadin peptides, DQ protein, and TCR are warranted to unravel the basis of immunogenicity and variability contributed by the genetic polymorphisms. Homology modeling of HLA and TCR done using Swiss Model and iTASSER, respectively. Molecular interactions of eight common deamidated immune-dominant gliadin with HLA-DQ allotypes and specific TCR gene pairs were evaluated. Docking of the three structures was performed with ClusPro2.0 and ProDiGY was used to predict binding energies. Effects of known allelic polymorphisms and reported susceptibility SNPs were predicted on protein–protein interactions. CD susceptible allele, HLA-DQ2.5 was shown to have considerable binding affinity to 33-mer gliadin (ΔG = − 13.9; Kd = 1.5E − 10) in the presence of TRAV26/TRBV7. Higher binding affinity was predicted (ΔG = − 14.3, Kd = 8.9E − 11) when TRBV28 was replaced with TRBV20 paired with TRAV4 suggesting its role in CD predisposition. SNP rs12722069 at HLA-DQ8 that codes Arg76α forms three H-bonds with Glu12 and two H-bonds with Asn13 of DQ2 restricted gliadin in the presence of TRAV8-3/TRBV6. None of the HLA-DQ polymorphisms was found to be in linkage disequilibrium with reported CD susceptibility markers. Haplotypic presentations of rs12722069-G, rs1130392-C, rs3188043-C and rs4193-A with CD reported SNPs were observed in sub-ethnic groups. Highly polymorphic sites of HLA alleles and TCR variable regions could be utilized for better risk prediction models in CD. Therapeutic strategies by identifying inhibitors or blockers targeting specific gliadin:HLA-DQ:TCR binding sites could be investigated.
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Data Availability
The datasets generated/analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
SS and SK acknowledge DST-FIST India, for providing financial support to the Department of Human Genetics and Molecular Medicine (SR/FST/LS-I/2017/49-C) and Department of Biochemistry, Central University of Punjab, Bathinda, India. PB is supported by the junior research fellowship from DST Inspire Fellowship [DST/INSPIRE/Fellowship/2019/IF190501]. AKS acknowledges the Council of Scientific and Industrial Research, for CSIR-SRF fellowship.
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We acknowledge financial supports from Department of Science and Technology-Science and Research Board (DST-SERB), Govt. of India (#ECR/2016/001660) and University Grants Commission, New Delhi, India (30–4/2014-BSR), to SS.
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SS and RC conceptualized and designed the study. PB, RC, AKS and PP performed the in silico data generation and analyses. PB and AKS generated the molecular structures. PB, SK and SS interpreted the results. PB, AKS and SS wrote the manuscript. SK and SS supervised the study and critically reviewed the findings. All the authors reviewed the manuscript. RC is now deceased.
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10528_2023_10377_MOESM3_ESM.tif
Supplementary file3 (TIF 1783 kb)—HLA DQ2/8 allele and TCR allelic polymorphism molecular interactome with gliadin residues (a) HLADQ2.5 (b) HLA DQ2.2 (c) HLA DQ8 (d-i) TRBV7-2 and (ii) TRBV20
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Banerjee, P., Chaudhary, R., Singh, A.K. et al. Specific Genetic Polymorphisms Contributing in Differential Binding of Gliadin Peptides to HLA-DQ and TCR to Elicit Immunogenicity in Celiac Disease. Biochem Genet 61, 2457–2480 (2023). https://doi.org/10.1007/s10528-023-10377-x
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DOI: https://doi.org/10.1007/s10528-023-10377-x