Abstract
CD1 molecules present lipid antigens to T-cells in early stages of immune responses. Whereas CD1‒lipid‒T-cell receptors interactions are reasonably understood, molecular details on initial trafficking and loading of lipids onto CD1 proteins are less complete. We present a molecular dynamics (MD) study of human CD1d, the isotype that activates iNKT cells. MD simulations and calculations of properties and Poisson-Boltzmann electrostatic potentials were used to explore the dynamics of the antigen-binding domain of the apo-form, CD1d complexes with three lipid–antigens that activate iNKT cells and CD1d complex with GM2AP, a protein that assists lipid loading onto CD1 molecules in endosomes/lysosomes. The study was done at pH 7 and 4.5, values representative of strongly acidic environments in endosomal compartments. Our findings revealed dynamic features of the entrance to the hydrophobic channels of CD1d modulated by two α helices with sensitivity to the type of lipid. We also found lipid- and pH-dependent dynamic changes in three exposed tryptophans unique to CD1d among the five human CD1 isotypes. On the basis of modelled structures, our data also revealed external effects produced by the helper protein GM2AP only when it interacts in its open form, thus suggesting that the own assistant protein also adapts conformation to association with CD1d.
Highlights
The adaptive responses of human immune system against hazards associated to a large diversity of molecules crucially depends on their recognition to trigger signaling events
cluster of differentiation 1 (CD1) and major histocompatibility complex (MHC)-I proteins are in charge of presenting lipid- and peptide-antigens, respectively, to specific T-cell receptors (TCRs) to trigger immune responses
The β2m domain is needed for the functional expression of CD1 proteins on the cell surface [4]
Summary
The adaptive responses of human immune system against hazards associated to a large diversity of molecules crucially depends on their recognition to trigger signaling events. Antigen-presenting proteins and T-cell receptors (TCRs) are major players in this initial stage [1]. The recognition of peptide fragments originated at foreign or host proteins presented by major histocompatibility complex (MHC) class I and II molecules has long been known and is reasonably understood [1,2,3]. The recognition of lipid antigens is less well characterized. Lipid antigens are presented by cluster of differentiation 1 (CD1) molecules to TCRs for T-cell activation [4]. Considerable advances have been made in recent years towards understanding the mechanisms of this activation mainly throughout the study of CD1-lipid-TCR interactions [5,6], significant gaps still remain in our knowledge about the initial loading of lipid antigens onto CD1 proteins
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