Crystal structure of human CD1e reveals a groove suited for lipid-exchange processes

Abstract

CD1e is the only human CD1 protein existing in soluble form in the late endosomes of dendritic cells, where it facilitates the processing of glycolipid antigens that are ultimately recognized by CD1b-restricted T cells. The precise function of CD1e remains undefined, thus impeding efforts to predict the participation of this protein in the presentation of other antigens. To gain insight into its function, we determined the crystal structure of recombinant CD1e expressed in human cells at 2.90-Å resolution. The structure revealed a groove less intricate than in other CD1 proteins, with a significantly wider portal characterized by a 2 Å-larger spacing between the α1 and α2 helices. No electron density corresponding to endogenous ligands was detected within the groove, despite the presence of ligands unequivocally established by native mass spectrometry in recombinant CD1e. Our structural data indicate that the water-exposed CD1e groove could ensure the establishment of loose contacts with lipids. In agreement with this possibility, lipid association and dissociation processes were found to be considerably faster with CD1e than with CD1b. Moreover, CD1e was found to mediate in vitro the transfer of lipids to CD1b and the displacement of lipids from stable CD1b-antigen complexes. Altogether, these data support that CD1e could have evolved to mediate lipidexchange/editing processes with CD1b and point to a pathway whereby the repertoire of lipid antigens presented by human dendritic cells might be expanded.3D structure | glycolipid antigen presentation | human CD1b | lipid antigen editing | lipid transfer protein F our transmembrane CD1 molecules (CD1a, are expressed in different cell-specific combinations by human immune cells and, among these, in dendritic cells (DCs), the professional antigen-presenting cells (APCs). These proteins present self or microbial lipid antigens to T cells, thus participating in innate and adaptive immunity (1, 2). Myeloid DCs also express a fifth isoform, CD1e, which indirectly participates in glycolipid antigen presentation. This protein has been found to facilitate the processing of complex mycobacterial hexamannosylated phosphatidylinositol (PIM 6 ) by lysosomal α-mannosidase into dimannosylated forms (PIM 2 ) that activate CD1b-restricted T-cell clones (3).In several respects, CD1e behaves differently from the other human CD1 family members. After biosynthesis, all membraneanchored CD1 molecules reach the Golgi compartments. Apart from CD1d, which is also delivered directly to endosomes (4), CD1a-d molecules are then transported to the plasma membrane, where they have been shown to bind some antigens. Subsequently, CD1 molecules are constitutively internalized into the endocytic network, where they capture antigenic ligands (4). Finally, the CD1-antigen complexes cycle back to the plasma membrane to activate specific T lymphocytes. In contrast, CD1e remains exclusively intracellular. After reaching the Golgi compartments, CD1e is addressed to sorting endosomes and from there to CD1...

Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells

“…A similar two-branched arrangement of A′ and F′ is seen in CD1e, the only CD1 isoform not expressed on the cell surface. Compared with CD1d, CD1a, and CD1b, the portal into the groove in CD1e is widely exposed, consistent with its known role in lipid transfer processes inside lysosomes (6).…”

“…Structurally, the main differences between these CD1 isoforms lie in the architecture of their lipophilic ligand binding grooves. Whereas all CD1 isoforms share a highly conserved A′ channel (or pocket) for binding C18-C26 acyl chains, specialization is provided by further connecting channels (2)(3)(4)(5)(6)(7). In CD1a, the A′ channel is "fused" to a wide and shallow F′ channel, enabling binding of lipopeptides such as mycobacterial didehydroxymycobactin (DDM) (8).…”

Deciphering the Role of CD1e Protein in Mycobacterial Phosphatidyl-myo-inositol Mannosides (PIM) Processing for Presentation by CD1b to T Lymphocytes

“…Although CD1e/PIM association has been shown by isoelectric focusing experiments (7,9), the mechanisms by which CD1e protein participates in PIM processing and influences the immune responses remains to be precisely determined. PIM exist naturally in the mycobacterial envelope as a mixture of different acyl forms, including mono-, di-, tri-, and tetra-acylated forms (17).…”

“…Thus, CD1e is an important modulator of both group 1 and group 2 CD1-restricted responses influencing the lipid antigen availability as well as the generation and persistence of CD1-lipid complexes (8). The crystal structure of human recombinant sCD1e (rsCD1e) at 2.90 Å resolution revealed that CD1e displays a main portal wider than that of other CD1 molecules as well as a less intricate groove, allowing accommodation of a variety of lipid antigens and facilitating the rapid exchange of bound lipids (9). Recent studies have implicated saposins in CD1 lipid antigen loading and presentation.…”

“…Both the multiple effects of CD1e on antigen presentation (8) and its structural characteristics (9) suggest that CD1e might have evolved to mediate lipid exchange/editing processes. Although CD1e/PIM association has been shown by isoelectric focusing experiments (7,9), the mechanisms by which CD1e protein participates in PIM processing and influences the immune responses remains to be precisely determined.…”