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A HLA-DRB supertype chart with potential overlapping peptide binding function.

Mohanapriya A, Nandagond S, Shapshak P, Kangueane U, Kangueane P - Bioinformation (2010)

Bottom Line: HLA-DRB alleles are class II alleles that are associated with CD4+ T-cell immune response.Definition of DRB supertypes using binding data is limited to few (about 29) known alleles (< 5% of all known DRB alleles).Hence, we describe a strategy using structurally defined virtual pockets to group all known DRB alleles with regard to their overlapping peptide binding specificity.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Informatics, Pondicherry 607 402, India; VITU, Vellore, Tamil Nadu 632 014, India.

ABSTRACT
HLA-DRB alleles are class II alleles that are associated with CD4+ T-cell immune response. DRB alleles are polymorphic and currently there are about 622 named in the IMGT/HLA sequence database. Each allele binds short peptides with high sensitivity and specificity. However, it has been suggested that majority of HLA alleles can be covered within few HLA supertypes, where different members of a supertype bind similar peptides showing distinct repertoires. Definition of DRB supertypes using binding data is limited to few (about 29) known alleles (< 5% of all known DRB alleles). Hence, we describe a strategy using structurally defined virtual pockets to group all known DRB alleles with regard to their overlapping peptide binding specificity.

No MeSH data available.


Grouping showing that the 622 DRB alleles accounts for 569 unique pockets
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Figure 7: Grouping showing that the 622 DRB alleles accounts for 569 unique pockets

Mentions: The binding groove in DRB molecules is formed by alpha and betachains (Figure 2). It accommodates peptides of length 12-35 [13]. Thepeptides bound to the groove have an extended conformation in classII unlike class I. The sequence similarity between defined class IIalleles is more than 70% and hence their structural similarity is high(Figure 5). The receptor backbone is highly similar and only theirside-chain orientations vary. Therefore, the peptide binding specificityis determined by the side chains influenced by polymorphism of theMHC alleles. Mohanapriya and colleagues (2009) defined virtualpockets using HERP extracted from HLA-peptide structuralcomplexes [13]. The hypothesis is that the 25 residues at the HERPforming the virtual pockets are deterministic of peptide binding and itsspecificity. The high degree of sequence homology between knownDRB alleles and hence their structural similarity suggests the influenceof polymorphic residues at the virtual pockets to determine peptidespecificity (Figure 6). We thus theoretically grouped the known 622DRB alleles using virtual pockets defined from structural datasets. Thegrouping (Figure 4) using the procedure illustrated in Figure 3produced 73 groups consisting of at least 2 alleles covering about 300alleles. Thus, the 73 groups exhibit overlapping peptide bindingfunction. This grouping is validated using known peptides (32 peptidesbind to DRB1*1101 and DRB1 *1104 and 6 peptides bind toDRB1*1301 and DRB1*1302) that are clustered within the samegroups in this study. The data presented here serves in general as aframework for understanding peptide binding overlap in particular forHLA-DRB supertype definition and groupings. Each DRB allelecontains nine virtual pockets by definition. Thus, the 622 DRB allelestheoretically contain a pool of 5598 virtual pockets made of HERPresidues in the dataset. The current analysis shows that the 622 DRBalleles accounts for only 569 unique pockets (Figure 7). Thisconstitutes only about 10% of theoretically possible virtual pocketssuggesting overlap of virtual pockets among 90% of the remainingpocket combinations. Thus, the study demonstrates the possible degreeof overlap within virtual pockets for potential functional overlapamong DRB alleles. The described framework finds application in thedesign of epitopes with cross reactivity across DRB specific ethnicpopulation towards peptide vaccine development.


A HLA-DRB supertype chart with potential overlapping peptide binding function.

Mohanapriya A, Nandagond S, Shapshak P, Kangueane U, Kangueane P - Bioinformation (2010)

Grouping showing that the 622 DRB alleles accounts for 569 unique pockets
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2957767&req=5

Figure 7: Grouping showing that the 622 DRB alleles accounts for 569 unique pockets
Mentions: The binding groove in DRB molecules is formed by alpha and betachains (Figure 2). It accommodates peptides of length 12-35 [13]. Thepeptides bound to the groove have an extended conformation in classII unlike class I. The sequence similarity between defined class IIalleles is more than 70% and hence their structural similarity is high(Figure 5). The receptor backbone is highly similar and only theirside-chain orientations vary. Therefore, the peptide binding specificityis determined by the side chains influenced by polymorphism of theMHC alleles. Mohanapriya and colleagues (2009) defined virtualpockets using HERP extracted from HLA-peptide structuralcomplexes [13]. The hypothesis is that the 25 residues at the HERPforming the virtual pockets are deterministic of peptide binding and itsspecificity. The high degree of sequence homology between knownDRB alleles and hence their structural similarity suggests the influenceof polymorphic residues at the virtual pockets to determine peptidespecificity (Figure 6). We thus theoretically grouped the known 622DRB alleles using virtual pockets defined from structural datasets. Thegrouping (Figure 4) using the procedure illustrated in Figure 3produced 73 groups consisting of at least 2 alleles covering about 300alleles. Thus, the 73 groups exhibit overlapping peptide bindingfunction. This grouping is validated using known peptides (32 peptidesbind to DRB1*1101 and DRB1 *1104 and 6 peptides bind toDRB1*1301 and DRB1*1302) that are clustered within the samegroups in this study. The data presented here serves in general as aframework for understanding peptide binding overlap in particular forHLA-DRB supertype definition and groupings. Each DRB allelecontains nine virtual pockets by definition. Thus, the 622 DRB allelestheoretically contain a pool of 5598 virtual pockets made of HERPresidues in the dataset. The current analysis shows that the 622 DRBalleles accounts for only 569 unique pockets (Figure 7). Thisconstitutes only about 10% of theoretically possible virtual pocketssuggesting overlap of virtual pockets among 90% of the remainingpocket combinations. Thus, the study demonstrates the possible degreeof overlap within virtual pockets for potential functional overlapamong DRB alleles. The described framework finds application in thedesign of epitopes with cross reactivity across DRB specific ethnicpopulation towards peptide vaccine development.

Bottom Line: HLA-DRB alleles are class II alleles that are associated with CD4+ T-cell immune response.Definition of DRB supertypes using binding data is limited to few (about 29) known alleles (< 5% of all known DRB alleles).Hence, we describe a strategy using structurally defined virtual pockets to group all known DRB alleles with regard to their overlapping peptide binding specificity.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Informatics, Pondicherry 607 402, India; VITU, Vellore, Tamil Nadu 632 014, India.

ABSTRACT
HLA-DRB alleles are class II alleles that are associated with CD4+ T-cell immune response. DRB alleles are polymorphic and currently there are about 622 named in the IMGT/HLA sequence database. Each allele binds short peptides with high sensitivity and specificity. However, it has been suggested that majority of HLA alleles can be covered within few HLA supertypes, where different members of a supertype bind similar peptides showing distinct repertoires. Definition of DRB supertypes using binding data is limited to few (about 29) known alleles (< 5% of all known DRB alleles). Hence, we describe a strategy using structurally defined virtual pockets to group all known DRB alleles with regard to their overlapping peptide binding specificity.

No MeSH data available.