HLA class II peptide-binding-region analysis reveals funneling of polymorphism in action

Abstract

Background: HLA-class II proteins hold important roles in key physiological processes. The purpose of this study was to compile all class II alleles reported in human population and investigate patterns in pocket variants and their combinations, focusing on the peptide-binding region (PBR). Methods: For this purpose, all protein sequences of DPA1, DQA1, DPB1, DQB1 and DRB1 were selected and filtered, in order to have full PBR sequences. Proportional representation was used for pocket variants while population data were also used. Results: All pocket variants and PBR sequences were retrieved and analyzed based on the preference of amino acids and their properties in all pocket positions. The observed number of pocket variants combinations was much lower than the possible inferred, suggesting that PBR formation is under strict funneling. Also, although class II proteins are very polymorphic, in the majority of the reported alleles in all populations, a significantly less polymorphic pocket core was found. Conclusions: Pocket variability of five HLA class II proteins was studied revealing favorable properties of each protein. The actual PBR sequences of HLA class II proteins appear to be governed by restrictions that lead to the establishment of only a fraction of the possible combinations and the polymorphism recorded is the result of intense funneling based on function. © 2021 European Federation of Immunological Societies