4nt6

HLA-C*0801 Crystal Structure

spinqualitylabelsall models 4nt6, resolution 1.84Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4nt6 is a 3 chain structure with sequence from Homo sapiens and Influenza A virus (A/Boston/115JC/2009(H1N1)). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.84Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease HLAC_HUMAN B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2). Disease susceptibility is associated with variants affecting the gene represented in this entry. Allele C*06:02 presents a melanocyte autoantigen ADAMTSL5 (VRSRRCLRL) to Valpha3S1/Vbeta13S1 TCR on CD8-positive T cells, and may trigger an autoimmune response against melanocytes. Function HLAC_HUMAN Antigen-presenting major histocompatibility complex class I (MHCI) molecule with an important role in reproduction and antiviral immunity (PubMed:11172028, PubMed:20104487, PubMed:20439706, PubMed:20972337, PubMed:24091323, PubMed:28649982, PubMed:29312307). In complex with B2M/beta 2 microglobulin displays a restricted repertoire of self and viral peptides and acts as a dominant ligand for inhibitory and activating killer immunoglobulin receptors (KIRs) expressed on NK cells (PubMed:16141329). In an allogeneic setting, such as during pregnancy, mediates interaction of extravillous trophoblasts with KIR on uterine NK cells and regulate trophoblast invasion necessary for placentation and overall fetal growth (PubMed:20972337, PubMed:24091323). During viral infection, may present viral peptides with low affinity for KIRs, impeding KIR-mediated inhibition through peptide antagonism and favoring lysis of infected cells (PubMed:20439706). Presents a restricted repertoire of viral peptides on antigen-presenting cells for recognition by alpha-beta T cell receptor (TCR) on HLA-C-restricted CD8-positive T cells, guiding antigen-specific T cell immune response to eliminate infected cells, particularly in chronic viral infection settings such as HIV-1 or CMV infection (PubMed:11172028, PubMed:20104487, PubMed:28649982). Both the peptide and the MHC molecule are recognized by TCR, the peptide is responsible for the fine specificity of antigen recognition and MHC residues account for the MHC restriction of T cells (By similarity). Typically presents intracellular peptide antigens of 9 amino acids that arise from cytosolic proteolysis via proteasome. Can bind different peptides containing allele-specific binding motifs, which are mainly defined by anchor residues at position 2 and 9. Preferentially displays peptides having a restricted repertoire of hydrophobic or aromatic amino acids (Phe, Ile, Leu, Met, Val and Tyr) at the C-terminal anchor (PubMed:25311805, PubMed:8265661).[UniProtKB:P04439] ALLELE C*01:02: The peptide-bound form interacts with KIR2DL2 and KIR2DL3 inhibitory receptors on NK cells. The low affinity peptides compete with the high affinity peptides impeding KIR-mediated inhibition and favoring lysis of infected cells (PubMed:20439706). Presents to CD8-positive T cells a CMV epitope derived from UL83/pp65 (RCPEMISVL), an immediate-early antigen necessary for initiating viral replication (PubMed:12947002). ALLELE C*04:01: Presents a conserved HIV-1 epitope derived from env (SFNCGGEFF) to memory CD8-positive T cells, eliciting very strong IFNG responses (PubMed:20104487). Presents CMV epitope derived from UL83/pp65 (QYDPVAALF) to CD8-positive T cells, triggering T cell cytotoxic response (PubMed:12947002). ALLELE C*05:01: Presents HIV-1 epitope derived from rev (SAEPVPLQL) to CD8-positive T cells, triggering T cell cytotoxic response. ALLELE C*06:02: In trophoblasts, interacts with KIR2DS2 on uterine NK cells and triggers NK cell activation, including secretion of cytokines such as GMCSF that enhances trophoblast migration. ALLELE C*07:02: Plays an important role in the control of chronic CMV infection. Presents immunodominant CMV epitopes derived from IE1 (LSEFCRVL and CRVLCCYVL) and UL28 (FRCPRRFCF), both antigens synthesized during immediate-early period of viral replication. Elicits a strong anti-viral CD8-positive T cell immune response that increases markedly with age. ALLELE C*08:01: Presents viral epitopes derived from CMV UL83 (VVCAHELVC) and IAV M1 (GILGFVFTL), triggering CD8-positive T cell cytotoxic response. ALLELE C*12:02: Presents CMV epitope derived from UL83 (VAFTSHEHF) to CD8-positive T cells. ALLELE C*15:02: Presents CMV epitope derived from UL83 CC (VVCAHELVC) to CD8-positive T cells, triggering T cell cytotoxic response. Publication Abstract from PubMed Cytotoxic T lymphocytes recognizing conserved peptide epitopes are crucial in the protection against influenza A virus (IAV) infection. The CD8 T cell response against the M158-66 (GILGFVFTL) matrix protein epitope is immunodominant when restricted by HLA-A*02, a major histocompatibility complex (MHC) expressed by approximately half of the human population. Herein, we report that the GILGFVFTL peptide is restricted by multiple HLA-C*08 alleles as well. We observed that M158-66 was able to elicit CTL responses in both HLA-A*02 and -C*08 positive individuals; and that GILGFVFTL-specific CTLs in individuals expressing both restriction elements were distinct and not cross-reactive. The crystal structure of GILGFVFTL/HLA-C*08:01 was solved at 1.84A and comparison with the known GILGFVFTL/HLA-A*02:01 structure revealed that the antigen bound both complexes in near-identical conformation, accommodated by binding pockets shaped from shared as well as unique residues. This discovery of degenerate peptide presentation by both HLA-A and HLA-C allelic variants eliciting unique CTL responses to IAV infection contributes fundamental knowledge with important implications for vaccine development strategies. IMPORTANCE: The presentation of influenza A virus peptide to elicit immunity is thought to be narrowly restricted, with a single peptide presented by a specific HLA molecule. In this study, we show that the same influenza A peptide can be more broadly presented by both HLA-A and HLA-C molecules. This discovery may help to explain the differences in immunity to influenza A between individuals and populations, and also aid in the design of vaccines. The immunodominant Influenza A virus M158-66 CTL epitope exhibits degenerate class I MHC restriction in humans.,Choo JA, Liu J, Toh X, Grotenbreg GM, Ren EC J Virol. 2014 Jul 2. pii: JVI.00855-14. PMID:24990997 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-2 microglobulin 3D structures

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