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Structural basis for the differential classification of HLA-A6802 and HLA-A6801 into the A2 and A3 supertypes.

ABSTRACT: High polymorphism is one of the most important features of human leukocyte antigen (HLA) alleles, which were initially classified by serotyping but have recently been re-grouped into supertypes according to their peptide presentation properties. Two relatively prevalent HLA alleles HLA-A*6801 and HLA-A*6802, are classified into the same serotype HLA-A68. However, based on their distinct peptide-binding characteristics, HLA-A*6801 is grouped into A3 supertype, whereas HLA-A*6802 belongs to A2 supertype, similar to HLA-A*0201. Thusfar, the structural basis of the different supertype definitions of these serotyping-identical HLA alleles remains largely unknown. Herein, we determined the structures of HLA-A*6801 and HLA-A*6802 presenting three typical A3 and A2 supertype-restricted peptides, respectively. The binding capabilities of these peptides to HLA-A*6801, HLA-A*6802, and HLA-A*0201 were analyzed. These data indicate that the similar conformations of the residues within the F pocket contribute to close-related peptide binding features of HLA-A*6802 and HLA-A*0201. However, the overall structure and the peptide conformation of HLA-A*6802 are more similar to HLA-A*6801 rather than HLA-A*0201 which illuminates the similar serotype grouping of HLA-A*6802 and HLA-A*6801. Our findings are helpful for understanding the divergent peptide presentation and virus-specific CTL responses impacted by MHC micropolymorphisms and also elucidate the molecular basis of HLA supertype definitions.

SUBMITTER: Niu L

PROVIDER: S-EPMC7112617 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Structural basis for the differential classification of HLA-A6802 and HLA-A6801 into the A2 and A3 supertypes.

Niu Ling L Cheng Hao H Zhang Shihong S Tan Shuguang S Zhang Yudan Y Qi Jianxun J Liu Jun J Gao George F GF

Molecular immunology 20130406 3-4

High polymorphism is one of the most important features of human leukocyte antigen (HLA) alleles, which were initially classified by serotyping but have recently been re-grouped into supertypes according to their peptide presentation properties. Two relatively prevalent HLA alleles HLA-A*6801 and HLA-A*6802, are classified into the same serotype HLA-A68. However, based on their distinct peptide-binding characteristics, HLA-A*6801 is grouped into A3 supertype, whereas HLA-A*6802 belongs to A2 sup ...[more]

PMID: 23566939

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Project description:BackgroundClass I major histocompatibility complex (MHC) molecules bind, and present to T cells, short peptides derived from intracellular processing of proteins. The peptide repertoire of a specific molecule is to a large extent determined by the molecular structure accommodating so-called main anchor positions of the presented peptide. These receptors are extremely polymorphic, and much of the polymorphism influences the peptide-binding repertoire. However, despite this polymorphism, class I molecules can be clustered into sets of molecules that bind largely overlapping peptide repertoires. Almost a decade ago we introduced this concept of clustering human leukocyte antigen (HLA) alleles and defined nine different groups, denominated as supertypes, on the basis of their main anchor specificity. The utility of this original supertype classification, as well several other subsequent arrangements derived by others, has been demonstrated in a large number of epitope identification studies.ResultsFollowing our original approach, in the present report we provide an updated classification of HLA-A and -B class I alleles into supertypes. The present analysis incorporates the large amount of class I MHC binding data and sequence information that has become available in the last decade. As a result, over 80% of the 945 different HLA-A and -B alleles examined to date can be assigned to one of the original nine supertypes. A few alleles are expected to be associated with repertoires that overlap multiple supertypes. Interestingly, the current analysis did not identify any additional supertype specificities.ConclusionAs a result of this updated analysis, HLA supertype associations have been defined for over 750 different HLA-A and -B alleles. This information is expected to facilitate epitope identification and vaccine design studies, as well as investigations into disease association and correlates of immunity. In addition, the approach utilized has been made more transparent, allowing others to utilize the classification approach going forward.

Project description:Ebolavirus (EBOV) is responsible for one of the most fatal diseases encountered by mankind. Cellular T-cell responses have been implicated to be important in providing protection against the virus. Antigenic variation can result in viral escape from immune recognition. Mapping targets of immune responses among the sequence of viral proteins is, thus, an important first step towards understanding the immune responses to viral variants and can aid in the identification of vaccine targets. Herein, we performed a large-scale, proteome-wide mapping and diversity analyses of putative HLA supertype-restricted T-cell epitopes of Zaire ebolavirus (ZEBOV), the most pathogenic species among the EBOV family.All publicly available ZEBOV sequences (14,098) for each of the nine viral proteins were retrieved, removed of irrelevant and duplicate sequences, and aligned. The overall proteome diversity of the non-redundant sequences was studied by use of Shannon's entropy. The sequences were predicted, by use of the NetCTLpan server, for HLA-A2, -A3, and -B7 supertype-restricted epitopes, which are relevant to African and other ethnicities and provide for large (~86%) population coverage. The predicted epitopes were mapped to the alignment of each protein for analyses of antigenic sequence diversity and relevance to structure and function. The putative epitopes were validated by comparison with experimentally confirmed epitopes.ZEBOV proteome was generally conserved, with an average entropy of 0.16. The 185 HLA supertype-restricted T-cell epitopes predicted (82 (A2), 37 (A3) and 66 (B7)) mapped to 125 alignment positions and covered ~24% of the proteome length. Many of the epitopes showed a propensity to co-localize at select positions of the alignment. Thirty (30) of the mapped positions were completely conserved and may be attractive for vaccine design. The remaining (95) positions had one or more epitopes, with or without non-epitope variants. A significant number (24) of the putative epitopes matched reported experimentally validated HLA ligands/T-cell epitopes of A2, A3 and/or B7 supertype representative allele restrictions. The epitopes generally corresponded to functional motifs/domains and there was no correlation to localization on the protein 3D structure. These data and the epitope map provide important insights into the interaction between EBOV and the host immune system.

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Structural basis for the differential classification of HLA-A6802 and HLA-A6801 into the A2 and A3 supertypes.

Publications

Structural basis for the differential classification of HLA-A6802 and HLA-A6801 into the A2 and A3 supertypes.

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Structural basis for the differential classification of HLA-A*6802 and HLA-A*6801 into the A2 and A3 supertypes.

Publications

Structural basis for the differential classification of HLA-A*6802 and HLA-A*6801 into the A2 and A3 supertypes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Structural basis for the differential classification of HLA-A6802 and HLA-A6801 into the A2 and A3 supertypes.

Structural basis for the differential classification of HLA-A6802 and HLA-A6801 into the A2 and A3 supertypes.