Structural reorganization of the antigen-binding groove of human CD1b for presentation of mycobacterial sulfoglycolipids

L F Garcia-Alles (1) , A Collmann (2) , C Versluis (3) , B Lindner (4) , J Guiard (1) , Laurent Maveyraud (1) , E Huc (1) , Jin S. Im (5) , S Sansano (2) , T Brando (1) , S Julien (1) , J Prandi (1) , M Gilleron (1) , S A Porcelli (5) , H de La Salle (6) , Albert J. R. Heck (3) , L Mori (2) , G Puzo (1) , L Mourey (1) , G de Libero (2)

1 IPBS - Institut de pharmacologie et de biologie structurale
2 University Hospital Basel [Basel]
3 Universiteit Utrecht / Utrecht University [Utrecht]
4 Forschungszentrum Borstel - Research Center Borstel
5 Albert Einstein College of Medicine [New York]
6 Biologie des Cellules Dendritiques Humaines

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-Å 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.

Mots clés: groove shrinking; CD1b mutant transfectant; T lymphocyte activation; diacylglycerol endogenous ligand

Domaines: Biologie structurale [q-bio.BM]; Biologie moléculaire; Biotechnologies

L F Garcia-Alles, A Collmann, C Versluis, B Lindner, J Guiard, et al.. Structural reorganization of the antigen-binding groove of human CD1b for presentation of mycobacterial sulfoglycolipids. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108 (43), pp.17755 - 17760. ⟨10.1073/pnas.1110118108⟩. ⟨hal-03003377⟩