TY - JOUR
T1 - Structural reorganization of the antigen-binding groove of human CD1b for presentation of mycobacterial sulfoglycolipids
AU - Garcia-Alles, Luis F.
AU - Collmann, Anthony
AU - Versluis, Cees
AU - Lindner, Buko
AU - Guiard, Julie
AU - Maveyraud, Laurent
AU - Huca, Emilie
AU - Im, Jin S.
AU - Sansano, Sebastiano
AU - Brando, Thérèse
AU - Julien, Sylviane
AU - Prandi, Jacques
AU - Gilleron, Martine
AU - Porcelli, Steven A.
AU - De La Salle, Henri
AU - Heck, Albert J.R.
AU - Mori, Lucia
AU - Puzo, Germain
AU - Mourey, Lionel
AU - De Libero, Gennaro
PY - 2011/10/25
Y1 - 2011/10/25
N2 - 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 ligandinduced conformational changes that, together with pocket intricacy, endows CD1b with the required molecular plasticity to present a broad range of structurally diverse antigens.
AB - 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 ligandinduced conformational changes that, together with pocket intricacy, endows CD1b with the required molecular plasticity to present a broad range of structurally diverse antigens.
KW - CD1b mutant transfectant
KW - Diacylglycerol endogenous ligand
KW - Groove shrinking
KW - T lymphocyte activation
KW - Three-dimensional structure
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U2 - 10.1073/pnas.1110118108
DO - 10.1073/pnas.1110118108
M3 - Article
C2 - 22006319
AN - SCOPUS:80055065064
SN - 0027-8424
VL - 108
SP - 17755
EP - 17760
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 43
ER -