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Zooming into the binding groove of HLA molecules: which positions and which substitutions change peptide binding most?

van Deutekom HW, Keşmir C - Immunogenetics (2015)

Bottom Line: We found that the effect of a single substitution in the peptide-binding groove depends on the substituted position and the amino acids involved.Additionally, we show that a single substitution in HLA-B molecules has more effect on the peptide-binding repertoire compared to that in HLA-A molecules.This provides an (alternative) explanation for the larger polymorphism of HLA-B molecules compared to HLA-A molecules.

View Article: PubMed Central - PubMed

Affiliation: Theoretical Biology and Bioinformatics, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands, h.w.vandeutekom@amc.uva.nl.

ABSTRACT
Human leukocyte antigen (HLA) genes are the most polymorphic genes in the human genome. Almost all polymorphic residues are located in the peptide-binding groove, resulting in different peptide-binding preferences. Whether a single amino acid change can alter the peptide-binding repertoire of an HLA molecule has never been shown. To experimentally quantify the contribution of a single amino acid change to the peptide repertoire of even a single HLA molecule requires an immense number of HLA peptide-binding measurements. Therefore, we used an in silico method to study the effect of single mutations on the peptide repertoires. We predicted the peptide-binding repertoire of a large set of HLA molecules and used the overlap of the peptide-binding repertoires of each pair of HLA molecules that differ on a single position to measure how much single substitutions change the peptide binding. We found that the effect of a single substitution in the peptide-binding groove depends on the substituted position and the amino acids involved. The positions that alter peptide binding most are the most polymorphic ones, while those that are hardly variable among HLA molecules have the lowest effect on the peptide repertoire. Although expected, the relationship between functional divergence and polymorphism of HLA molecules has never been shown before. Additionally, we show that a single substitution in HLA-B molecules has more effect on the peptide-binding repertoire compared to that in HLA-A molecules. This provides an (alternative) explanation for the larger polymorphism of HLA-B molecules compared to HLA-A molecules.

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Peptide-binding motifs. For those HLA molecules discussed in the text, the top 1,000 best predicted binders out of 105 natural peptides are presented in a sequence logo. These motifs are very similar to the motifs on the MHC motif viewer website (Rapin et al. 2008), where motifs from other HLA molecules are also available
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Fig2: Peptide-binding motifs. For those HLA molecules discussed in the text, the top 1,000 best predicted binders out of 105 natural peptides are presented in a sequence logo. These motifs are very similar to the motifs on the MHC motif viewer website (Rapin et al. 2008), where motifs from other HLA molecules are also available

Mentions: Yague et al. (1998) showed that, although HLA-B*39:01 and HLA-B*39:10 differ only at position 67, HLA-B*39:10 has a more hydrophobic B pocket than its closest neighbor HLA-B*39:01. Since HLA-B*39:10 peptide-binding data was not used to train the netMHCpan method, we investigated whether the predicted peptide-binding repertoires of these two molecules reflect the reported difference. In Fig. 2, we plot the predicted binders for these two HLA molecules in the form of a sequence logo. Indeed, our predictions suggest a very dominant preference for Proline on the second anchor residue for HLA- B*39:10 in contrast to the preference for basic residues for HLA-B*39:01 (Fig. 2, upper panel). Out of the 1,000 predicted binders for HLA-B*39:10 and those for HLA-B*39:01, only 318 are present in both peptide-binding repertoires, suggesting that the binding preferences of these two HLA molecules are largely distinct.Fig. 2


Zooming into the binding groove of HLA molecules: which positions and which substitutions change peptide binding most?

van Deutekom HW, Keşmir C - Immunogenetics (2015)

Peptide-binding motifs. For those HLA molecules discussed in the text, the top 1,000 best predicted binders out of 105 natural peptides are presented in a sequence logo. These motifs are very similar to the motifs on the MHC motif viewer website (Rapin et al. 2008), where motifs from other HLA molecules are also available
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4498290&req=5

Fig2: Peptide-binding motifs. For those HLA molecules discussed in the text, the top 1,000 best predicted binders out of 105 natural peptides are presented in a sequence logo. These motifs are very similar to the motifs on the MHC motif viewer website (Rapin et al. 2008), where motifs from other HLA molecules are also available
Mentions: Yague et al. (1998) showed that, although HLA-B*39:01 and HLA-B*39:10 differ only at position 67, HLA-B*39:10 has a more hydrophobic B pocket than its closest neighbor HLA-B*39:01. Since HLA-B*39:10 peptide-binding data was not used to train the netMHCpan method, we investigated whether the predicted peptide-binding repertoires of these two molecules reflect the reported difference. In Fig. 2, we plot the predicted binders for these two HLA molecules in the form of a sequence logo. Indeed, our predictions suggest a very dominant preference for Proline on the second anchor residue for HLA- B*39:10 in contrast to the preference for basic residues for HLA-B*39:01 (Fig. 2, upper panel). Out of the 1,000 predicted binders for HLA-B*39:10 and those for HLA-B*39:01, only 318 are present in both peptide-binding repertoires, suggesting that the binding preferences of these two HLA molecules are largely distinct.Fig. 2

Bottom Line: We found that the effect of a single substitution in the peptide-binding groove depends on the substituted position and the amino acids involved.Additionally, we show that a single substitution in HLA-B molecules has more effect on the peptide-binding repertoire compared to that in HLA-A molecules.This provides an (alternative) explanation for the larger polymorphism of HLA-B molecules compared to HLA-A molecules.

View Article: PubMed Central - PubMed

Affiliation: Theoretical Biology and Bioinformatics, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands, h.w.vandeutekom@amc.uva.nl.

ABSTRACT
Human leukocyte antigen (HLA) genes are the most polymorphic genes in the human genome. Almost all polymorphic residues are located in the peptide-binding groove, resulting in different peptide-binding preferences. Whether a single amino acid change can alter the peptide-binding repertoire of an HLA molecule has never been shown. To experimentally quantify the contribution of a single amino acid change to the peptide repertoire of even a single HLA molecule requires an immense number of HLA peptide-binding measurements. Therefore, we used an in silico method to study the effect of single mutations on the peptide repertoires. We predicted the peptide-binding repertoire of a large set of HLA molecules and used the overlap of the peptide-binding repertoires of each pair of HLA molecules that differ on a single position to measure how much single substitutions change the peptide binding. We found that the effect of a single substitution in the peptide-binding groove depends on the substituted position and the amino acids involved. The positions that alter peptide binding most are the most polymorphic ones, while those that are hardly variable among HLA molecules have the lowest effect on the peptide repertoire. Although expected, the relationship between functional divergence and polymorphism of HLA molecules has never been shown before. Additionally, we show that a single substitution in HLA-B molecules has more effect on the peptide-binding repertoire compared to that in HLA-A molecules. This provides an (alternative) explanation for the larger polymorphism of HLA-B molecules compared to HLA-A molecules.

Show MeSH