Abstract
CD1 molecules present lipid antigens for recognition by T-cell receptors (TCRs). Although a reasonably detailed picture of the CD1-lipid-TCR interaction exists, the initial steps regarding lipid loading onto and exchange between CD1 proteins remain elusive. The hydrophobic nature of lipids and the fact that CD1 molecules are unable to extract lipids from membranes raise the need for the assistance of helper proteins in lipid trafficking. However, the experimental study of this traffic in the endosomal compartments at which it occurs is so challenging that computational studies can help provide mechanistic insight into the associated processes. Here we present a multifaceted computational approach to obtain dynamic structural data on the human CD1d isotype. Conformational dynamics analysis shows an intrinsic flexibility associated with the protein architecture. Electrostatic properties together with molecular dynamics results for CD1d complexes with several lipids and helper proteins unravel the high dynamic plasticity of the antigen-binding site that is crucially favoured by acidic pH and the presence of helper proteins.
Highlights
cluster of differentiation 1 (CD1) molecules present lipid antigens for recognition by T-cell receptors (TCRs)
Significant differences in antigen-binding grooves and conformational dynamics are associated with similar structures in CD1d and major histocompatibility complex (MHC)-I
Human CD1d and MHC-I exhibit a similar architecture composed of two chains: an α chain comprised of α1, α2 and α3 domains and a non-covalently linked chain consisting of a β2-microglobulin (β2 m) domain (Fig. 1a)
Summary
CD1 molecules present lipid antigens for recognition by T-cell receptors (TCRs). a reasonably detailed picture of the CD1-lipid-TCR interaction exists, the initial steps regarding lipid loading onto and exchange between CD1 proteins remain elusive. CD1 molecules are MHC-I-like glycoproteins organised early according to sequence homology into two groups: group 1 is composed of CD1a, CD1b, CD1c, and CD1e and group 2 is composed of the single member CD1d9 Of these five CD1 isotypes, a-d are transmembrane proteins that present lipid antigens to TCRs at the cell surface, while CD1e remains intracellular, is the only CD1 member that exists in soluble form and can apparently function as a lipid transfer protein (LTP)[10]. The domain α3 begins at residue 187 in CD1d and at residue 185 in MHC-I. show here that despite their structural similarity, the architecture of CD1d presents essential differences in its conformational dynamics with respect to that of MHC-I
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