Dataset Information

The CD1 size problem: lipid antigens, ligands, and scaffolds.

ABSTRACT: Whereas research on CD1d has emphasized a few glycosyl ceramides, the broader family of four human CD1 antigen-presenting molecules binds hundreds of distinct self-lipids. Individual lipid types bind within CD1 grooves in different ways, such that they partially fill the groove, match the groove volume, or protrude substantially from the groove. These differing modes of binding can now be connected to differing immunological functions, as individual lipids can act as stimulatory antigens, inhibitory ligands, or space-filling scaffolds. Because each type of CD1 protein folds to produce antigen-binding grooves with differing sizes and shapes, CD1a, CD1b, CD1c, CD1d, and CD1e have distinct mechanisms of capturing self-lipids and exchanging them for foreign lipids. The size discrepancy between endogeneous lipids and groove volume is most pronounced for CD1b. Recent studies show that the large CD1b cavity can simultaneously bind two self-lipids, the antigen, and its scaffold lipid, which can be exchanged for one large bacterial lipid. In this review, we will highlight recent studies showing how cells regulate lipid antigen loading and the roles CD1 groove structures have in control of the presentation of chemically diverse lipids to T cells.

SUBMITTER: Ly D

PROVIDER: S-EPMC4160407 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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The CD1 size problem: lipid antigens, ligands, and scaffolds.

Ly Dalam D Moody D Branch DB

Cellular and molecular life sciences : CMLS 20140801 16

Whereas research on CD1d has emphasized a few glycosyl ceramides, the broader family of four human CD1 antigen-presenting molecules binds hundreds of distinct self-lipids. Individual lipid types bind within CD1 grooves in different ways, such that they partially fill the groove, match the groove volume, or protrude substantially from the groove. These differing modes of binding can now be connected to differing immunological functions, as individual lipids can act as stimulatory antigens, inhibi ...[more]

PMID: 24658584

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Project description:BackgroundT cell receptors (TCRs) can recognize diverse lipid and metabolite antigens presented by MHC-like molecules CD1 and MR1, and the molecular basis of many of these interactions has not been determined. Here we applied our protein docking algorithm TCRFlexDock, previously developed to perform docking of TCRs to peptide-MHC (pMHC) molecules, to predict the binding of αβ and γδ TCRs to CD1 and MR1, starting with the structures of the unbound molecules.ResultsEvaluating against TCR-CD1d complexes with crystal structures, we achieved near-native structures in the top 20 models for two out of four cases, and an acceptable-rated prediction for a third case. We also predicted the structure of an interaction between a MAIT TCR and MR1-antigen that has not been structurally characterized, yielding a top-ranked model that agreed remarkably with a characterized TCR-MR1-antigen structure that has a nearly identical TCR α chain but a different β chain, highlighting the likely dominance of the conserved α chain in MR1-antigen recognition. Docking performance was improved by re-training our scoring function with a set of TCR-pMHC complexes, and for a case with an outlier binding mode, we found that alternative docking start positions improved predictive accuracy. We then performed unbound docking with two mycolyl-lipid specific TCRs that recognize lipid-bound CD1b, which represent a class of interactions that is not structurally characterized. Highly-ranked models of these complexes showed remarkable agreement between their binding topologies, as expected based on their shared germline sequences, while differences in residue-level interactions with their respective antigens point to possible mechanisms underlying their distinct specificities.ConclusionsTogether these results indicate that flexible docking simulations can provide accurate models and atomic-level insights into TCR recognition of MHC-like molecules presenting lipid and other small molecule antigens.

Dataset Information

The CD1 size problem: lipid antigens, ligands, and scaffolds.

Publications

The CD1 size problem: lipid antigens, ligands, and scaffolds.

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