Specific Genetic Polymorphisms Contributing in Differential Binding of Gliadin Peptides to HLA-DQ and TCR to Elicit Immunogenicity in Celiac Disease

dc.contributor.authorBanerjee, Pratibha
dc.contributor.authorChaudhary, Ramprasad
dc.contributor.authorSingh, Atul Kumar
dc.contributor.authorParulekar, Pratima
dc.contributor.authorKumar, Shashank
dc.contributor.authorSenapati, Sabyasachi
dc.date.accessioned2024-01-16T14:23:24Z
dc.date.accessioned2024-08-13T10:34:17Z
dc.date.available2024-01-16T14:23:24Z
dc.date.available2024-08-13T10:34:17Z
dc.date.issued2023-04-27T00:00:00
dc.description.abstractImmunogenicity 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 (?G = ?�13.9; Kd = 1.5E�?�10) in the presence of TRAV26/TRBV7. Higher binding affinity was predicted (?G = ?�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 Arg76? 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. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.en_US
dc.identifier.doi10.1007/s10528-023-10377-x
dc.identifier.issn62928
dc.identifier.urihttps://doi.org/10.1007/s10528-023-10377-x
dc.identifier.urihttps://kr.cup.edu.in/handle/32116/2924
dc.language.isoen_USen_US
dc.publisherSpringeren_US
dc.subjectDifferential bindingen_US
dc.subjectGliadinen_US
dc.subjectHLA-DQ alleleen_US
dc.subjectImmunogenicityen_US
dc.subjectMolecular dockingen_US
dc.subjectT-cell receptoren_US
dc.titleSpecific Genetic Polymorphisms Contributing in Differential Binding of Gliadin Peptides to HLA-DQ and TCR to Elicit Immunogenicity in Celiac Diseaseen_US
dc.title.journalBiochemical Geneticsen_US
dc.typeArticleen_US
dc.type.accesstypeClosed Accessen_US

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