Most efforts in characterizing HLA-DQ binding specificities have been directed towards a few selected molecules, such as DQA1*05:01-DQB1*02:01 (also known as DQ2) or DQA1*03:01-DQB1*03:02 (DQ8) because of their association with disease.19–21 The data published by Wang et al.7 aim to be more comprehensive in terms of human population coverage, and they include binding data for the six most common allelic variants across different ethnicities.
The HLA-DQ sequence motifs identified by NNAlign are shown in Fig. 2. In contrast to the DP variants, which appear to share a common supertypical pattern, the DQ molecules show very little overlap in specificity. There do not appear to be common amino acid preferences, and the anchors are found at different positions within the 9-mer core. In particular, DQA1*01:01-DQB1*05:01 shows a strong preference for aromatic residues (F, W, Y) at P5, and secondary anchors at P6 and P7. The only previous report addressing the binding motif of this molecule8 also found a dominant anchor characterized by a preference for W and F, but placed this anchor at P4, and is generally in disagreement with our findings on other positions. The binding motif for DQA1*01:02-DQB1*06:02 appears loose, with several amino acids allowed at most positions. Previous reports22,23 identified mainly a P4–P6–P9 anchor spacing, with small and hydrophobic residues at P4, hydrophobic/aliphatic amino acids such as I, L, M, V at P6, and small residues like A and S at P9. Similar amino acid preferences are reflected in the binding motif detected by NNAlign, with additional anchors at P3 and P7. The only pair of molecules that appear to have a somewhat similar specificity is composed of DQA1*03:01-DQB1*03:02 and DQA1*04:01-DQB1*04:02. Both show a dominant anchor at P9, with preference for the acidic residues E and D. Additionally, they both show a preference for hydrophobic amino acids at P6, and mainly for A or E at P8. The strong acidic anchor at P9 was observed before.19,24 In the case of DQA1*05:01-DQB1*02:01, previous studies describe a motif with P1 and P9 binding pockets with hydrophobic/aromatic preferences, and acidic residues in the centre of the core, particularly at P4, P6 and P7.8,24–28 Besides the hydrophobic/aromatic P1–P9, NNAlign places the strongest anchor at P7, but with preferences for glutamic acid (E) also at P6 and P8. Finally, the somewhat peculiar sequence motif of DQA1*05:01-DQB1*03:01 seems to just prefer small amino acids such as A, G and S, especially on the central positions of the core, in agreement with the motif previously suggested for this molecule.8
It is evident that the peptide-binding specificities for HLA-DQ variants are much more diverse than for HLA-DP variants. In particular, the strong hydrophobic/aromatic P1 anchor that generally characterizes all known HLA-DR and DP molecules is not observed here. There appears to be no general pattern in the spacing of the anchors, as well as in the kinds of permitted amino acids. In particular, we find a preference for acidic amino acids close to or at the C-terminal of the binding motif for three of the six molecules, and generally, the motifs seem rather promiscuous, with several residues allowed in the binding groove of the MHC.