Crystal Structure of Bovine CD1b3 with Endogenously Bound Ligands

Gottardi, Enrico; Wang, Jing; Mac, Thien-Thi; Versluis, Cees; Bhowruth, Veemal; Besra, Gurdyal S.; Heck, Albert J. R.; Rhijn, Ildiko Van; Zajonc, Dirk M.

doi:10.4049/jimmunol.1000042

Cited by 15 publications

(18 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, PC/SM/ULe ligands might be expected to adopt variable conformations and orientations within the groove if the greater interhelical separation results in weaker contacts between ligand acyl tails and hydrophobic groove residues. In our opinion, this hypothesis is unlikely because fatty acid tail portions should still be detected in the relatively narrow A′ pocket, similar to what was reported for endogenous PC and phosphatidylethanolamine (PE) ligands bound with variable orientations to bovine CD1b3 (29).…”

Section: Resultssupporting

confidence: 76%

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

Garcia-Alles

Giacometti

Versluis

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Resultssupporting

confidence: 76%

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

Garcia-Alles

Giacometti

Versluis

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although still compatible with two residues that coincidentally contacted the Ac 2 SGL-specific TCR, our combined functional and structural data rather suggest that Glu80 and Tyr151 are important because they sustain F′ closure and spacer displacement, alterations that would be mandatory for presentation of diacylsulfoglycolipids. Interestingly, F′ closure implicating the same two residues has been observed in the crystal structure of bovine CD1b3 (31). Such mechanism of groove tailoring to ligand structure thus differed from a proposed mechanism involving an alternate side-chain conformation of Phe84 (6).…”

Section: Discussionmentioning

confidence: 86%

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

Garcia-Alles

Collmann

Versluis

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

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.three-dimensional structure | groove shrinking | diacylglycerol endogenous ligand | T lymphocyte activation | CD1b mutant transfectant T lymphocytes have developed the capacity to recognize as antigens a large variety of molecules including peptides, (glyco)lipids, and phosphorylated metabolites (1). Specific recognition of peptides or lipids by T-cell receptors (TCR) occurs when these molecules form antigenic complexes with dedicated antigen-presenting molecules belonging to MHC or CD1 families, respectively. Diversity has forced the immune system to develop appropriate strategies to present antigens in immunogenic form. Polymorphic MHC molecules cope with the peptide repertoire by constraining the ligand conformational space (2). Less clear is how the immune system adapts to the large glycolipid antigenic range and forms antigenic complexes using the functionally nonpolymorphic CD1 molecules.Human antigen-presenting cells (APC) display the CD1a, CD1b, CD1c, and CD1d proteins on their plasma membranes (1, 3). CD1 ectodomains consist of a heavy chain, which folds into three extracellular domains (α1-α3) noncovalently associated with β2-microglobulin (4). Antigen-binding grooves nestle between the α1 and α2 domains and are mostly lined by hydrophobic residues. This allows the antigenic lipids to be anchored via their hydrophobic chains, so that polar motifs protrude toward the aqueous milieu. Consequently, polar heads but not hydrophobic tails are assumed to establish stimulatory contacts with TCRs. Nevertheless, modifications in the lipid chains may also indirectly impact on TCR recognition (5).The number, shape, and conn...

show abstract

“…The structure of bovine CD1b3 (boCD1b3) with endogenously bound lipids PC and phosphatidylethanolamine (PE) identified a binding groove that is identical in size to that of human CD1b (Girardi et al 2010). A doughnut-shaped A′ pocket that circles around the conserved A′ pole (Leu12 and Phe70) directly connects with the solvent accessible F′ pocket (Fig.…”

Section: Human/mouse Cd1 Isotype-specific Adaptationsmentioning

confidence: 99%

The CD1 family: serving lipid antigens to T cells since the Mesozoic era

Zajonc

2016

Immunogenetics

Self Cite

View full text Add to dashboard Cite

Class I-like CD1 molecules are in a family of antigen-presenting molecules that bind lipids and lipopeptides, rather than peptides for immune surveillance by T cells. Since CD1 lacks the high degree of polymorphism found in their major histocompatibility complex (MHC) class I molecules, different species express different numbers of CD1 isotypes, likely to be able to present structurally diverse classes of lipid antigens. In this review, we will present a historical overview of the structures of the different human CD1 isotypes and also discuss species-specific adaptations of the lipid-binding groove. We will discuss how single amino acid changes alter the shape and volume of the CD1 binding groove, how these minor changes can give rise to different numbers of binding pockets, and how these pockets affect the lipid repertoire that can be presented by any given CD1 protein. We will compare the structures of various lipid antigens and finally, we will discuss recognition of CD1-presented lipid antigens by antigen receptors on T cells (TCRs).

show abstract

Crystal Structure of Bovine CD1b3 with Endogenously Bound Ligands

Cited by 15 publications

References 57 publications

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

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

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

The CD1 family: serving lipid antigens to T cells since the Mesozoic era

Contact Info

Product

Resources

About