Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease

Abstract

Celiac disease, also known as celiac sprue, is a gluten-induced autoimmune-like disorder of the small intestine, which is strongly associated with HLA-DQ2. The structure of DQ2 complexed with an immunogenic epitope from gluten, QLQPFPQPELPY, has been determined to 2.2-Å resolution by x-ray crystallography. The glutamate at P6, which is formed by tissue transglutaminase-catalyzed deamidation, is an important anchor residue as it participates in an extensive hydrogen-bonding network involving Lys-␤71 of DQ2. The gluten peptide-DQ2 complex retains critical hydrogen bonds between the MHC and the peptide backbone despite the presence of many proline residues in the peptide that are unable to participate in amide-mediated hydrogen bonds. Positioning of proline residues such that they do not interfere with backbone hydrogen bonding results in a reduction in the number of registers available for gluten peptides to bind to MHC class II molecules and presumably impairs the likelihood of establishing favorable side-chain interactions. The HLA association in celiac disease can be explained by a superior ability of DQ2 to bind the biased repertoire of proline-rich gluten peptides that have survived gastrointestinal digestion and that have been deamidated by tissue transglutaminase. Finally, surface-exposed proline residues in the proteolytically resistant ligand were replaced with functionalized analogs, thereby providing a starting point for the design of orally active agents for blocking gluten-induced toxicity.

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

“…Actually, the crystal structure of DQ2cis shows b71Lys participating in this pocket and facilitating, via water-mediated hydrogen bonds, the anchoring of an acidic residue. 29 DQ2cis and -trans are among the few molecules that have a distinct preference for pocket 7: acidic, aliphatic and aromatic, but no basic residues. This is attributed to the presence of b70Arg/b71Lys, unique only to DQB1*0201/0202/0203 rendering the surface electrostatic potential of such proteins in pockets 4 and 7 very positive, attracting thus negatively charged anchor residues of the antigenic peptide.…”

“…24,35 The recently determined crystal structures of DQ2cis (DQA1*0501-DQB1*0201) 29 and DQ8cis (DQA1*0301-DQB1*0302) 25 were used as base molecules. The program Quanta (Accelrys, San Diego, CA, USA) was used to obtain a complete structure by providing the missing amino-acid residues from the crystal structure (for example, b105-112), as well as missing atoms from certain residues.…”

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

“…16), DQ8 (ref. 17) and DQ2, 18 together with peptide-binding data and studies of naturally processed peptides selected by these T1D-associated molecules 12,19 permitted the description of the peptide-binding motifs for these alleles. However, the HLA-DR8 peptide repertoire has only been partially described 20 and the binding motif remains unknown.…”

Soluble HLA-DQ2 expressed in S2 cells copurifies with a high affinity insect cell derived protein

“…DCB-45 is a highly acidic protein (pI 4.27) and HLA-DQ2 has a strong preference for binding negatively charged residues in several of its anchor positions (Kim et al 2004). We therefore investigated whether the sDQ2/DCB-45 binding is also involving the peptide binding groove of sDQ2.…”

“…This sequence contains alanine in position 1, which is not expected to be favorable due to its small size and the preference that HLA-DQ2 has for bulky hydrophobic anchor residues at this position (van de Wal et al 1996;Vartdal et al 1996). Notably, peptide binding to HLA-DQ2 is characterized by contributions from anchor residues in position 1, 4, 6, 7, and 9 (Kim et al 2004). This is in contrast to peptide binding to HLA-DR molecules which has a dominant contribution of the P1 anchor (Jardetzky et al 1990;Stern et al 1994).…”