5ksb
T15-DQ8.5-glia-gamma1 complex
Structural highlights
FunctionDQA1_HUMAN Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal miroenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading. Publication Abstract from PubMedIn HLA-DQ8-associated celiac disease, TRAV26-2+-TRBV9+ and TRAV8-3+-TRBV6+ T cells recognize the immunodominant DQ8-glia-alpha1 epitope, whereupon a non-germline-encoded arginine residue played a key role in binding HLA-DQ8-glia-alpha1. Whether distinct T cell receptor (TCR) recognition modes exist for gliadin epitopes remains unclear. TCR repertoire analysis revealed populations of HLA-DQ8-glia-alpha1 and HLA-DQ8.5-glia-gamma1 restricted TRAV20+-TRBV9+ T cells that did not possess a non-germline-encoded arginine residue. The crystal structures of a TRAV20+-TRBV9+ TCR-HLA-DQ8-glia-alpha1 complex and two TRAV20+-TRBV9+ TCR-HLA-DQ8.5-glia-gamma1 complexes were determined. This revealed that the differential specificity toward DQ8-glia-alpha1 and DQ8.5-glia-gamma1 was governed by CDR3beta-loop-mediated interactions. Surprisingly, a germline-encoded arginine residue within the CDR1alpha loop of the TRAV20+ TCR substituted for the role of the non-germline-encoded arginine in the TRAV26-2+-TRBV9+ and TRAV8-3+-TRBV6+ TCRs. Thus, in celiac disease, the responding TCR repertoire is driven by a common mechanism that selects for structural elements within the TCR that have convergent binding solutions in HLA-DQ8-gliadin recognition. Diverse T Cell Receptor Gene Usage in HLA-DQ8-Associated Celiac Disease Converges into a Consensus Binding Solution.,Petersen J, Kooy-Winkelaar Y, Loh KL, Tran M, van Bergen J, Koning F, Rossjohn J, Reid HH Structure. 2016 Aug 23. pii: S0969-2126(16)30221-0. doi:, 10.1016/j.str.2016.07.010. PMID:27568928[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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