5tez | pdb_00005tez
TCR F50 recgonizing M1-HLA-A2
Structural highlights
FunctionM1_I34A1 Plays critical roles in virus replication, from virus entry and uncoating to assembly and budding of the virus particle. M1 binding to ribonucleocapsids (RNPs) in nucleus seems to inhibit viral transcription. Interaction of viral NEP with M1-RNP is thought to promote nuclear export of the complex, which is targeted to the virion assembly site at the apical plasma membrane in polarized epithelial cells. Interactions with NA and HA may bring M1, a non-raft-associated protein, into lipid rafts. Forms a continuous shell on the inner side of the lipid bilayer in virion, where it binds the RNP. During virus entry into cell, the M2 ion channel acidifies the internal virion core, inducing M1 dissociation from the RNP. M1-free RNPs are transported to the nucleus, where viral transcription and replication can take place.[1] Determines the virion's shape: spherical or filamentous. Clinical isolates of influenza are characterized by the presence of significant proportion of filamentous virions, whereas after multiple passage on eggs or cell culture, virions have only spherical morphology. Filamentous virions are thought to be important to infect neighboring cells, and spherical virions more suited to spread through aerosol between hosts organisms.[2] Publication Abstract from PubMedInfluenza A virus (IAV) causes an acute infection in humans that is normally eliminated by CD8+ cytotoxic T lymphocytes. Individuals expressing the major histocompatibility complex (MHC) class I molecule HLA-A2 produce cytotoxic T lymphocytes bearing T cell receptors (TCRs) that recognize the immunodominant IAV epitope GILGFVFTL (GIL). Most GIL-specific TCRs utilize alpha/beta pairs encoded by the TRAV27/TRBV19 gene combination to recognize this relatively featureless peptide epitope (canonical TCRs). However, ~40% of GIL-specific TCRs express a wide variety of other TRAV/TRBV combinations (non-canonical TCRs). To investigate the structural underpinnings of this remarkable diversity, we determined the crystal structure of a non-canonical GIL-specific TCR (F50) expressing the TRAV13-1/TRBV27 gene combination bound to GIL-HLA-A2 to 1.7 A resolution. Comparison of the F50-GIL-HLA-A2 complex with the previously publishedcomplex formed by a canonical TCR (JM22) revealed that F50 and JM22 engage GIL-HLA-A2 in markedly different orientations. These orientations are distinguished by crossing angles of TCR to peptide-MHC of 29o for F50 versus 69o for JM22, and by a focus by F50 on the C-terminus rather than the center of the MHC alpha1 helix for JM22. In addition, F50, unlike JM22, uses a tryptophan instead of an arginine to fill a critical notch between GIL and the HLA-A2 alpha 2 helix. The F50-GIL-HLA-A2 complex shows that there are multiple structurally distinct solutions to recognizing an identical peptide-MHC ligand with sufficient affinity to elicit a broad anti-IAV response that protects against viral escape and T cell clonal loss. Structural basis for clonal diversity of the human T cell response to a dominant influenza virus epitope.,Yang X, Chen G, Weng NP, Mariuzza RA J Biol Chem. 2017 Sep 20. pii: jbc.M117.810382. doi: 10.1074/jbc.M117.810382. PMID:28931605[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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