Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease.
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-A 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-beta71 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.
Kim
Chu-Young
CY
Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
Quarsten
Hanne
H
Bergseng
Elin
E
Khosla
Chaitan
C
Sollid
Ludvig M
LM
D002446:Celiac Disease / Q000276:immunology*; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005903:Gliadin / Q000737:chemistry / Q000276:immunology; D005983:Glutens / Q000737:chemistry* / Q000276:immunology; D006683:HLA-DQ Antigens / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D008024:Ligands; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011392:Proline / Q000737:chemistry; D017434:Protein Structure, Tertiary
D000939:Epitopes; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D008024:Ligands; D010455:Peptides; D005983:Glutens; D005903:Gliadin; D011392:Proline