The spectrum of HLA-DQ and HLA-DR alleles, 2006: a listing correlating sequence and structure with function

Abstract

The list of alleles in the HLA-DRB, HLA-DQA, and HLA-DQB gene loci has grown enormously since the last listing in this journal 8 years ago. Crystal structure determination of several human and mouse HLA class II alleles, representative of two gene loci in each species, enables a direct comparison of ortholog and paralog loci. A new numbering system is suggested, extending earlier suggestions by [Fremont et al. in Immunity 8:305-317, (1998)], which will bring in line all the structural features of various gene loci, regardless of animal species. This system allows for structural equivalence of residues from different gene loci. The listing also highlights all amino acid residues participating in the various functions of these molecules, from antigenic peptide binding to homodimer formation, CD4 binding, membrane anchoring, and cytoplasmic signal transduction, indicative of the variety of functions of these molecules. It is remarkable that despite the enormous number of unique alleles listed thus far (DQA = 22, DQB = 54, DRA = 2, and DRB = 409), there is invariance at many specific positions in man, but slightly less so in mouse or rat, despite their much lower number of alleles at each gene locus in the latter two species. Certain key polymorphisms (from substitutions to an eight-residue insertion in the cytoplasmic tail of certain DQB alleles) that have thus far gone unnoticed are highly suggestive of differences or diversities in function and thus call for further investigation into the properties of these specific alleles. This listing is amenable to supplementation by future additions of new alleles and the highlighting of new functions to be discovered, providing thus a unifying platform of reference in all animal species for the MHC class II allelic counterparts, aiding research in the field and furthering our understanding of the functions of these molecules.

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

“…All other known DQB molecules have His/Tyr at b30 and Tyr (except DQB*0601) at b37. 32 Because of the b30Ser, the DQ2 cis-and trans-molecules accept, besides small aliphatic residues, acidic ones as well. By contrast, DQ8cis and -trans accept only small aliphatic residues in this pocket.…”

“…The minimized structure thus obtained has the peptide in a polyproline II helical conformation as expected of all peptides bound to MHC II molecules. The numbering of the residues in the amino-acid sequences of the DQA and DQB molecules was carried out according to Bondinas et al, 32 as it ensures structural equivalence across MHC class II loci within the same and throughout different species. All three modeled structures will be deposited in the Protein Data Bank.…”

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

“…These pockets contain mostly polymorphic residues, making different alleles to bind a specific group of residues in each pocket. 1 Peptides bind with the corresponding pocket residues of the binding groove via specific interactions of the core residues at relative positions P1, 4, 6 and 9 (anchor residues). For every MHC class II allele, each pocket has a specificity for different residues, determining the binding affinity of the peptides.…”

Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

“…In the case of MHC class II, peptides of variable length are bound specifically via interactions with distinct pockets within the peptide binding cleft. Among the hundreds of different class II alleles, these peptide binding pockets include polymorphic residues, such that each allele accommodates a specific set of residues for a given binding pocket, thereby determining its binding affinity for peptide sequences (1). As such, each class II allele binds and presents a distinct set of peptides based on the specific amino acid residues that comprise its peptide binding pockets.…”