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PDBsum entry 4nqc
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Immune system
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PDB id
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4nqc
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Contents |
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255 a.a.
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96 a.a.
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263 a.a.
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185 a.a.
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240 a.a.
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198 a.a.
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References listed in PDB file
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Key reference
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Title
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T-Cell activation by transitory neo-Antigens derived from distinct microbial pathways.
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Authors
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A.J.Corbett,
S.B.Eckle,
R.W.Birkinshaw,
L.Liu,
O.Patel,
J.Mahony,
Z.Chen,
R.Reantragoon,
B.Meehan,
H.Cao,
N.A.Williamson,
R.A.Strugnell,
D.Van sinderen,
J.Y.Mak,
D.P.Fairlie,
L.Kjer-Nielsen,
J.Rossjohn,
J.Mccluskey.
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Ref.
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Nature, 2014,
509,
361-365.
[DOI no: ]
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PubMed id
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Abstract
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T cells discriminate between foreign and host molecules by recognizing distinct
microbial molecules, predominantly peptides and lipids. Riboflavin precursors
found in many bacteria and yeast also selectively activate mucosal-associated
invariant T (MAIT) cells, an abundant population of innate-like T cells in
humans. However, the genesis of these small organic molecules and their mode of
presentation to MAIT cells by the major histocompatibility complex (MHC)-related
protein MR1 (ref. 8) are not well understood. Here we show that MAIT-cell
activation requires key genes encoding enzymes that form
5-amino-6-d-ribitylaminouracil (5-A-RU), an early intermediate in bacterial
riboflavin synthesis. Although 5-A-RU does not bind MR1 or activate MAIT cells
directly, it does form potent MAIT-activating antigens via non-enzymatic
reactions with small molecules, such as glyoxal and methylglyoxal, which are
derived from other metabolic pathways. The MAIT antigens formed by the reactions
between 5-A-RU and glyoxal/methylglyoxal were simple adducts,
5-(2-oxoethylideneamino)-6-D-ribitylaminouracil (5-OE-RU) and
5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), respectively, which
bound to MR1 as shown by crystal structures of MAIT TCR ternary complexes.
Although 5-OP-RU and 5-OE-RU are unstable intermediates, they became trapped by
MR1 as reversible covalent Schiff base complexes. Mass spectra supported the
capture by MR1 of 5-OP-RU and 5-OE-RU from bacterial cultures that activate MAIT
cells, but not from non-activating bacteria, indicating that these MAIT antigens
are present in a range of microbes. Thus, MR1 is able to capture, stabilize and
present chemically unstable pyrimidine intermediates, which otherwise convert to
lumazines, as potent antigens to MAIT cells. These pyrimidine adducts are
microbial signatures for MAIT-cell immunosurveillance.
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