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Presentation of lipid antigens by CD1 glycoproteins.

ABSTRACT: CD1 molecules are a family of non-polymorphic, class I antigen-presenting glycoproteins, which bind and present amphiphilic lipid antigens for recognition to T cells. Two groups of CD1 molecules are involved in presentation of self and foreign lipid antigens: group 1 (CD1a, CD1b and CD1c) and group 2 (CD1d). Crystal structures of CD1a, CD1b and CD1d in complex with different ligands have revealed the key principles of lipid presentation and defined unique binding groove architectures for the individual CD1 isoforms, which enable binding and presentation of an enormous variety of lipids. Structural and biochemical insights into presentation of glycolipids by CD1d have led to the discovery of novel lipid antigens and to a broader understanding of the underlying structural and mechanistic principles of NKT cell stimulation. Some of these glycolipids show enhanced and more specific stimulatory properties and crystal structures have suggested further design strategies for elicitation of immuno-stimulatory compounds that may enable selective control of the secretion of regulatory T helper cytokines.

SUBMITTER: Schiefner A

PROVIDER: S-EPMC3096567 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Presentation of lipid antigens by CD1 glycoproteins.

Schiefner André A Wilson Ian A IA

Current pharmaceutical design 20090101 28

CD1 molecules are a family of non-polymorphic, class I antigen-presenting glycoproteins, which bind and present amphiphilic lipid antigens for recognition to T cells. Two groups of CD1 molecules are involved in presentation of self and foreign lipid antigens: group 1 (CD1a, CD1b and CD1c) and group 2 (CD1d). Crystal structures of CD1a, CD1b and CD1d in complex with different ligands have revealed the key principles of lipid presentation and defined unique binding groove architectures for the ind ...[more]

PMID: 19860680

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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

Presentation of lipid antigens by CD1 glycoproteins.

Publications

Presentation of lipid antigens by CD1 glycoproteins.

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