4h26

TCR interaction with peptide mimics of nickel offers structure insight to nickel contact allergy

spinqualitylabelsall models 4h26, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4h26 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.5Å Ligands: NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DRA_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 PubMed T cell-mediated allergy to Ni(++) is one of the most common forms of allergic contact dermatitis, but how the T-cell receptor (TCR) recognizes Ni(++) is unknown. We studied a TCR from an allergic patient that recognizes Ni(++) bound to the MHCII molecule DR52c containing an unknown self-peptide. We identified mimotope peptides that can replace both the self-peptide and Ni(++) in this ligand. They share a p7 lysine whose epsilonNH(2) group is surface-exposed when bound to DR52c. Whereas the TCR uses germ-line complementary-determining region (CDR)1/2 amino acids to dock in the conventional diagonal mode on the mimotope-DR52c complex, the interface is dominated by the TCR Vbeta CDR3 interaction with the p7 lysine. Mutations in the TCR CDR loops have similar effects on the T-cell response to either the mimotope or Ni(++) ligand. We suggest that the mimotope p7 lysine mimics Ni(++) in the natural TCR ligand and that MHCII beta-chain flexibility in the area around the peptide p7 position forms a common site for cation binding in metal allergies. T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy.,Yin L, Crawford F, Marrack P, Kappler JW, Dai S Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18517-22. doi:, 10.1073/pnas.1215928109. Epub 2012 Oct 22. PMID:23091041 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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