Structure of human CD1b with bound ligands at 2.3 Å, a maze for alkyl chains

Abstract

The human genome encodes five nonpolymorphic major histocompatibility complex class I-like glycoproteins, CD1a to CD1e, that present lipid antigens for specific recognition by T lymphocytes. Using single alkyl chain detergents, we developed a protocol to generate recombinant human CD1b-lipid complexes. We present here the crystal structures of CD1b in complex with either phosphatidylinositol or ganglioside GM2 at 2.3 A and 2.8 A resolutions, respectively. The antigen-binding groove houses four interlinked hydrophobic channels that are occupied by the alkyl chains of the glycolipid plus two detergent molecules. A distinct exit beneath the alpha 2 helix further contributes to the plasticity of the binding groove. These structures reveal the mechanism by which two alkyl chain lipids bind to CD1b, and how CD1b can adapt to ligands of different alkyl chain length. They also suggest how very long alkyl chains, such as those of mycolic acid, could be fully contained within the binding groove. These results extend the spectrum of potential CD1b ligands by revealing that, in addition to two alkyl chain lipids, mono-alkyl and triple-alkyl chain lipids can be accommodated in the binding groove.

The T cell antigen receptor expressed by Vα14iNKT cells has a unique mode of glycosphingolipid antigen recognition

“…This finding supports a critical role for the antigen's most rigid moiety (the carbohydrate unit), and it also suggests that recognition of glycolipid͞CD1d complexes is more likely to fit a lock-and-key model. This is further supported by the crystal structures of CD1b bound to glycolipids, where the polar head group of the antigens were found protruding toward the TCR (33,34), although similar observations were not made in the crystal structure of the CD1a͞sulfatide complex (38). Altogether, these data suggest that V␣14i NKT cells may have evolved a different way of sensing their environment.…”

“…First, the diversity of antigens naturally bound to CD1d is limited (32), and CD1 molecules are not polymorphic. Second, CD1-bound antigens are not exposed along the surface of the antigen-binding groove, and the hydrophilic head group is highly exposed only near the center of the groove (33,34). Third, many V␣14i NKT cells do not express CD4 or CD8, suggesting they may not require coreceptors (10).…”

Lipid–protein interactions: Biosynthetic assembly of CD1 with lipids in the endoplasmic reticulum is evolutionarily conserved

“…The daughter ions of m͞z 604.4 and 643.4 reflect the loss of a C18:1 acyl chain and phosphoinositol, respectively, from the 885. 3 [MϩH] ϩ ion. Thus, soluble mCD1d1-associated PI contains heterogeneous fatty acyl chains, which includes C36:2 (C16:0ϩC20:2, C18:0ϩC18:2, and C18:1ϩC18:1), C38:5 (C18:1ϩC20:4), C38:4 (C18:0ϩC20:4) identified based on CID analysis of the molecular ions and possibly C34:2, C36:3, C38:3, C40:5, and C40:6 deduced from the masses of the respective molecular ions.…”

“…The solution of the 3D structures of CD1a, CD1b, and CD1d reveals that they resemble the classical peptide antigenpresenting MHC molecules (2)(3)(4). In contrast to MHC molecules, the antigen-binding groove of CD1 is large, exclusively nonpolar, and hydrophobic (2)(3)(4) and hence has evolved to chaperone lipid antigens to the cell surface.…”

“…In contrast to MHC molecules, the antigen-binding groove of CD1 is large, exclusively nonpolar, and hydrophobic (2)(3)(4) and hence has evolved to chaperone lipid antigens to the cell surface. The majority of antigenic lipid binding to CD1 occurs within endocytic compartments (5)(6)(7)(8).…”