, Volume 59, Issue 7, pp 539-553
Date: 12 May 2007

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

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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.

Note added in the revised version: While the manuscript was under revision, a second work appeared within the year of 2006, implicating the H2-Aβ225Lys in the process of ubiquitination of these molecules, hence intricately involved with their lifetime on the cell membrane (Ohmura-Oshimo et al. 2006; Shin et al. 2006). While the residue is conserved in HLA-DQ/DR, we do not wish to mark this property in the Supplementary Tables before confirmation in the human system. This nevertheless, further demonstrates the utility of the Supplementary Tables to all interested researchers, as the tables can be amended as new properties are firmly established.