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


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          • The structure of HLA*6802 was determined for the first time.

          • F pocket contributes to similar peptide binding motif of HLA-A*6802 and HLA-A*0201.

          • Overall structure and the peptide conformation of HLA-A*6802 are more similar to HLA-A*6801 rather than HLA-A*0201.


          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.

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          Most cited references61

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          HLA class I supertypes: a revised and updated classification

          Background Class 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. Results Following 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. Conclusion As 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.
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            Structure of the human class I histocompatibility antigen, HLA-A2.

            The class I histocompatibility antigen from human cell membranes has two structural motifs: the membrane-proximal end of the glycoprotein contains two domains with immunoglobulin-folds that are paired in a novel manner, and the region distal from the membrane is a platform of eight antiparallel beta-strands topped by alpha-helices. A large groove between the alpha-helices provides a binding site for processed foreign antigens. An unknown 'antigen' is found in this site in crystals of purified HLA-A2.
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              A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC.

              The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.

                Author and article information

                Mol Immunol
                Mol. Immunol
                Molecular Immunology
                Elsevier Ltd.
                6 April 2013
                October 2013
                6 April 2013
                : 55
                : 3
                : 381-392
                [a ]CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
                [b ]University of Chinese Academy of Sciences, Beijing, China
                [c ]Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
                Author notes
                [* ]Corresponding authors at: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Tel.: +86 10 64807688; fax: +86 10 64807882. liuj333@ 123456gmail.com gaof@ 123456im.ac.cn
                Copyright © 2013 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                : 6 February 2013
                : 15 March 2013

                hla i, hla class i,pc, c-terminal position of the peptide,p2, position 2 from the n-terminus of the peptide,hla supertype,hla-a*6802,hla-a*6801,hla-a*0201,t cell


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