Proteopedia

8vz8

Crystal structure of mouse MAIT M2B TCR-MR1-5-OP-RU complexCrystal structure of mouse MAIT M2B TCR-MR1-5-OP-RU complex

Structural highlights

8vz8 is a 4 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.45Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HMR1_MOUSE Antigen-presenting molecule specialized in displaying microbial pyrimidine-based metabolites to alpha-beta T cell receptors (TCR) on innate-type mucosal-associated invariant T (MAIT) cells. In complex with B2M preferentially presents riboflavin-derived metabolites to semi-invariant TRAV1 TCRs on MAIT cells, guiding immune surveillance of the microbial metabolome at mucosal epithelial barriers (PubMed:15802267, PubMed:20581831). Signature pyrimidine-based microbial antigens are generated via non-enzymatic condensation of metabolite intermediates of the riboflavin pathway with by-products arising from other metabolic pathways such as glycolysis. Typical potent antigenic metabolites are 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil (5-OE-RU) and 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), products of condensation of 5-amino-6-D-ribityaminouracil (5-A-RU) with glyoxal or methylglyoxal by-products, respectively. May present microbial antigens to various TRAV1-negative MAIT cell subsets, providing for unique recognition of diverse microbes, including pathogens that do not synthesize riboflavin. Upon antigen recognition, elicits rapid innate-type MAIT cell activation to eliminate pathogenic microbes by directly killing infected cells (By similarity). During T cell development, drives thymic selection and post-thymic terminal differentiation of MAIT cells in a process dependent on commensal microflora (PubMed:12634786, PubMed:31113973). Acts as an immune sensor of cancer cell metabolome. May present a tumor-specific or -associated metabolite essential for cancer cell survival to a pan-cancer TCR on a non-MAIT CD8-positive T cell clone, triggering T cell-mediated killing of a wide range of cancer cell types (By similarity).[UniProtKB:Q95460][1] [2] [3] [4]

Publication Abstract from PubMed

Mucosal-associated invariant T (MAIT) cells can elicit immune responses against riboflavin-based antigens presented by the evolutionary conserved MHC class I related protein, MR1. While we have an understanding of the structural basis of human MAIT cell receptor (TCR) recognition of human MR1 presenting a variety of ligands, how the semi-invariant mouse MAIT TCR binds mouse MR1-ligand remains unknown. Here, we determine the crystal structures of 2 mouse TRAV1-TRBV13-2(+) MAIT TCR-MR1-5-OP-RU ternary complexes, whose TCRs differ only in the composition of their CDR3beta loops. These mouse MAIT TCRs mediate high affinity interactions with mouse MR1-5-OP-RU and cross-recognize human MR1-5-OP-RU. Similarly, a human MAIT TCR could bind mouse MR1-5-OP-RU with high affinity. This cross-species recognition indicates the evolutionary conserved nature of this MAIT TCR-MR1 axis. Comparing crystal structures of the mouse versus human MAIT TCR-MR1-5-OP-RU complexes provides structural insight into the conserved nature of this MAIT TCR-MR1 interaction and conserved specificity for the microbial antigens, whereby key germline-encoded interactions required for MAIT activation are maintained. This is an important consideration for the development of MAIT cell-based therapeutics that will rely on preclinical mouse models of disease.

Mouse mucosal-associated invariant T cell receptor recognition of MR1 presenting the vitamin B metabolite, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil.,Ciacchi L, Mak JYW, Le JP, Fairlie DP, McCluskey J, Corbett AJ, Rossjohn J, Awad W J Biol Chem. 2024 May;300(5):107229. doi: 10.1016/j.jbc.2024.107229. Epub 2024 , Mar 25. PMID:38537698[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Treiner E, Duban L, Bahram S, Radosavljevic M, Wanner V, Tilloy F, Affaticati P, Gilfillan S, Lantz O. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature. 2003 Mar 13;422(6928):164-9. PMID:12634786 doi:10.1038/nature01433
  2. ↑ Huang S, Gilfillan S, Cella M, Miley MJ, Lantz O, Lybarger L, Fremont DH, Hansen TH. Evidence for MR1 antigen presentation to mucosal-associated invariant T cells. J Biol Chem. 2005 Jun 3;280(22):21183-93. Epub 2005 Mar 31. PMID:15802267 doi:10.1074/jbc.M501087200
  3. ↑ Le Bourhis L, Martin E, Péguillet I, Guihot A, Froux N, Coré M, Lévy E, Dusseaux M, Meyssonnier V, Premel V, Ngo C, Riteau B, Duban L, Robert D, Huang S, Rottman M, Soudais C, Lantz O. Antimicrobial activity of mucosal-associated invariant T cells. Nat Immunol. 2010 Aug;11(8):701-8. PMID:20581831 doi:10.1038/ni.1890
  4. ↑ Koay HF, Gherardin NA, Xu C, Seneviratna R, Zhao Z, Chen Z, Fairlie DP, McCluskey J, Pellicci DG, Uldrich AP, Godfrey DI. Diverse MR1-restricted T cells in mice and humans. Nat Commun. 2019 May 21;10(1):2243. PMID:31113973 doi:10.1038/s41467-019-10198-w
  5. ↑ Ciacchi L, Mak JYW, Le JP, Fairlie DP, McCluskey J, Corbett AJ, Rossjohn J, Awad W. Mouse mucosal-associated invariant T cell receptor recognition of MR1 presenting the vitamin B metabolite, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil. J Biol Chem. 2024 May;300(5):107229. PMID:38537698 doi:10.1016/j.jbc.2024.107229

8vz8, resolution 3.45Å

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