4en3 | pdb_00004en3
Crystal structure of a human Valpha24(-) NKT TCR in complex with CD1d/alpha-galactosylceramide
Structural highlights
FunctionCD1D_HUMAN Antigen-presenting protein that binds self and non-self glycolipids and presents them to T-cell receptors on natural killer T-cells.[1] Publication Abstract from PubMedCD1d-mediated presentation of glycolipid antigens to T cells is capable of initiating powerful immune responses that can have a beneficial impact on many diseases. Molecular analyses have recently detailed the lipid antigen recognition strategies utilized by the invariant Valpha24-Jalpha18 TCR rearrangements of iNKT cells, which comprise a subset of the human CD1d-restricted T cell population. In contrast, little is known about how lipid antigens are recognized by functionally distinct CD1d-restricted T cells bearing different TCRalpha chain rearrangements. Here we present crystallographic and biophysical analyses of alpha-galactosylceramide (alpha-GalCer) recognition by a human CD1d-restricted TCR that utilizes a Valpha3.1-Jalpha18 rearrangement and displays a more restricted specificity for alpha-linked glycolipids than that of iNKT TCRs. Despite having sequence divergence in the CDR1alpha and CDR2alpha loops, this TCR employs a convergent recognition strategy to engage CD1d/alphaGalCer, with a binding affinity ( approximately 2 microM) almost identical to that of an iNKT TCR used in this study. The CDR3alpha loop, similar in sequence to iNKT-TCRs, engages CD1d/alphaGalCer in a similar position as that seen with iNKT-TCRs, however fewer actual contacts are made. Instead, the CDR1alpha loop contributes important contacts to CD1d/alphaGalCer, with an emphasis on the 4'OH of the galactose headgroup. This is consistent with the inability of Valpha24- T cells to respond to alpha-glucosylceramide, which differs from alphaGalCer in the position of the 4'OH. These data illustrate how fine specificity for a lipid containing alpha-linked galactose is achieved by a TCR structurally distinct from that of iNKT cells. The molecular basis for recognition of CD1d/alpha-galactosylceramide by a human non-Valpha24 T cell receptor.,Lopez-Sagaseta J, Kung JE, Savage PB, Gumperz J, Adams EJ PLoS Biol. 2012;10(10):e1001412. doi: 10.1371/journal.pbio.1001412. Epub 2012 Oct, 23. PMID:23109910[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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