Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 43, Pages 17755-17760Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1110118108
Keywords
three-dimensional structure; groove shrinking; diacylglycerol endogenous ligand; T lymphocyte activation; CD1b mutant transfectant
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Funding
- CNRS
- Universite Paul Sabatier
- Region Midi-Pyrenees
- European Regional Development Fund
- European Union
- Agence Nationale de la Recherche Emergence, France [ANR-07-EMPB-029-01]
- Swiss National Foundation [3100AO-122464/1]
- National Institutes of Health/National Institute of Allergy and Infectious Diseases [AI45889]
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The mechanisms permitting nonpolymorphic CD1 molecules to present lipid antigens that differ considerably in polar head and aliphatic tails remain elusive. It is also unclear why hydrophobic motifs in the aliphatic tails of some antigens, which presumably embed inside CD1 pockets, contribute to determinants for T-cell recognition. The 1.9-angstrom crystal structure of an active complex of CD1b and a mycobacterial diacylsulfoglycolipid presented here provides some clues. Upon antigen binding, endogenous spacers of CD1b, which consist of a mixture of diradylglycerols, moved considerably within the lipid-binding groove. Spacer displacement was accompanied by F' pocket closure and an extensive rearrangement of residues exposed to T-cell receptors. Such structural reorganization resulted in reduction of the A' pocket capacity and led to incomplete embedding of the methyl-ramified portion of the phthioceranoyl chain of the antigen, explaining why such hydrophobic motifs are critical for T-cell receptor recognition. Mutagenesis experiments supported the functional importance of the observed structural alterations for T-cell stimulation. Overall, our data delineate a complex molecular mechanism combining spacer repositioning and ligand-induced conformational changes that, together with pocket intricacy, endows CD1b with the required molecular plasticity to present a broad range of structurally diverse antigens.
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