van Deutekom Hanneke W M, Keşmir Can
Theoretical Biology and Bioinformatics, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands,
Immunogenetics. 2015 Aug;67(8):425-36. doi: 10.1007/s00251-015-0849-y. Epub 2015 Jun 4.
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.
人类白细胞抗原（HLA）基因是人类基因组中多态性最高的基因。几乎所有的多态性残基都位于肽结合凹槽中，导致不同的肽结合偏好。单个氨基酸的变化是否会改变HLA分子的肽结合库，此前从未得到证实。要通过实验量化单个氨基酸变化对单个HLA分子肽库的贡献，需要进行大量的HLA肽结合测量。因此，我们使用了一种计算机模拟方法来研究单个突变对肽库的影响。我们预测了大量HLA分子的肽结合库，并利用在单个位置上存在差异的每对HLA分子的肽结合库重叠情况，来衡量单个替换对肽结合的影响程度。我们发现，肽结合凹槽中单个替换的影响取决于替换位置和所涉及的氨基酸。对肽结合改变最大的位置是多态性最高的位置，而在HLA分子中几乎不变的位置对肽库的影响最小。尽管这是预期中的结果，但HLA分子功能差异与多态性之间的关系此前从未得到证实。此外，我们还表明，与HLA-A分子相比，HLA-B分子中的单个替换对肽结合库的影响更大。这为HLA-B分子比HLA-A分子具有更大的多态性提供了一种（另一种）解释。
