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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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The effect of substitutions in different HLA peptide-binding pockets. The positions are ordered according to the pockets, and several positions are represented in more than one pocket (Fig. 1c). The number in between brackets indicates the total number of positions within the pocket that are also among the 34 positions used by netMHCpan (Fig. 1d); note that this number also includes monomorphic positions
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Fig4: The effect of substitutions in different HLA peptide-binding pockets. The positions are ordered according to the pockets, and several positions are represented in more than one pocket (Fig. 1c). The number in between brackets indicates the total number of positions within the pocket that are also among the 34 positions used by netMHCpan (Fig. 1d); note that this number also includes monomorphic positions

Mentions: Nevertheless, being part of the B or F pocket does not necessarily imply that changing these positions would change the peptide-binding repertoire, because positions 24, 45, 70, and 99 of the B pocket and 77, 80, and 95 of the F pocket hardly change the functionality (Fig. 4).Fig. 4


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

van Deutekom HW, Keşmir C - Immunogenetics (2015)

The effect of substitutions in different HLA peptide-binding pockets. The positions are ordered according to the pockets, and several positions are represented in more than one pocket (Fig. 1c). The number in between brackets indicates the total number of positions within the pocket that are also among the 34 positions used by netMHCpan (Fig. 1d); note that this number also includes monomorphic positions
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: The effect of substitutions in different HLA peptide-binding pockets. The positions are ordered according to the pockets, and several positions are represented in more than one pocket (Fig. 1c). The number in between brackets indicates the total number of positions within the pocket that are also among the 34 positions used by netMHCpan (Fig. 1d); note that this number also includes monomorphic positions
Mentions: Nevertheless, being part of the B or F pocket does not necessarily imply that changing these positions would change the peptide-binding repertoire, because positions 24, 45, 70, and 99 of the B pocket and 77, 80, and 95 of the F pocket hardly change the functionality (Fig. 4).Fig. 4

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