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

Content Provider	Springer Nature Link
Author	van Deutekom, Hanneke W. M. Keşmir, Can
Copyright Year	2015
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.
Starting Page	425
Ending Page	436
Page Count	12
File Format	PDF
ISSN	00937711
Journal	Immunogenetics
Volume Number	67
Issue Number	8
e-ISSN	14321211
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2015-06-04
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	HLA molecules Binding groove Polymorphism Peptide binding Immunology Human Genetics Gene Function Cell Biology Allergology
Content Type	Text
Resource Type	Article
Subject	Genetics Immunology

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