Anatomy of CD1–lipid antigen complexes

Human and mouse CD1 proteins are MHC-like molecules that are expressed at the surface of antigen-presenting cells and bind lipids. The recent discovery of many classes of lipid antigens for CD1-restricted T cells implies that the CD1 system surveys cells for changes in their lipid content.Five crystal structures of CD1 proteins bound to lipids have now been solved. These show that the alkyl chains of antigens are inserted into a hydrophobic groove so that their carbohydrate or peptide moieties protrude for contact with T-cell receptors.The general mechanisms of antigen capture by CD1 and MHC proteins differ, as only CD1 uses a deeply buried hydrophobic surface to bind chemically diverse lipid antigens.CD1 grooves are composed of up to four antigen-binding pockets, which are known as the A′, C′, F′ and T′ pockets, and up to two antigen-entry portals that are known as the F′ and C′ portals.Glycolipid–CD1a and lipopeptide–CD1a structures show that the A′ pocket is narrow and has a blunt terminus, which allows it to function as a 'molecular ruler' that binds lipids with a defined alkyl chain length.CD1b proteins can bind antigens with a lipid component that is larger or smaller than the antigen-binding groove. This process probably involves chaperone lipids that bind together with small antigens and the ability of long antigens to protrude through portals so that they lie on the outer surface of the protein.Crystal structures show that CD1a, CD1b and CD1d markedly differ in the size, shape and connectivity of their antigen-binding pockets, which implies that each CD1 protein differs in its specificity for lipid ligands.