Crystal Structure of Mouse CD1: An MHC-Like Fold with a Large Hydrophobic Binding Groove

Abstract

CD1 represents a third lineage of antigen-presenting molecules that are distantly related to major histocompatibility complex (MHC) molecules in the immune system. The crystal structure of mouse CD1d1, corresponding to human CD1d, at 2.8 resolution shows that CD1 adopts an MHC fold that is more closely related to that of MHC class I than to that of MHC class II. The binding groove, although significantly narrower, is substantially larger because of increased depth and it has only two major pockets that are almost completely hydrophobic. The extreme hydrophobicity and shape of the binding site are consistent with observations that human CD1b and CD1c can present mycobacterial cell wall antigens, such as mycolic acid and lipoarabinomannans. However, mouse CD1d1 can present very hydrophobic peptides, but must do so in a very different way from MHC class Ia and class II molecules.

Human Invariant Vα24-JαQ TCR Supports the Development of CD1d-Dependent NK1.1+ and NK1.1− T Cells in Transgenic Mice

“…NKT cell clones recognize APC expressing either mouse or human CD1d, respectively (20). CD1d displays close structural similarities with MHC class I molecules; however, its Ag binding groove is very hydrophobic, compatible with its presenting functions for Ags with lipid compositions (21). Although the structure of the natural CD1d-associated ligand recognized by inv.…”

Cd1d–Glycolipid Tetramers

“…In the first place, all previous MHC heavy chains had been refolded with well characterized short peptides that could be produced in large quantity and high purity, and in many cases the crystal structure of the relevant MHC–peptide complex was known. In contrast, although the crystal structure of recombinant mouse CD1d had been solved 16, very little was known about the potential physical interactions between glycolipids and CD1d molecules. Even worse, preliminary attempts to measure the strength of interactions between purified CD1d molecules and α-GalCer by plasmon resonance technology had indicated a very short half-life 17, thereby suggesting that the production of stable tetramers might be difficult if not impossible.…”

Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

“…Located on a different chromosome than the MHC, five different CD1 genes encode CD1 molecules -CD1a, CD1b, CD1c, CD1d and CD1e -in humans, whereas only two homologues of CD1d (CD1d1 and CD1d2) are present in mice [2]. On the basis of the crystal structure of mouse CD1d1 [3], it is predicted that the fatty-acyl chains are buried in the hydrophobic pocket of the molecule with the hydrophilic head-group of the lipid antigen available outside the molecule for its interaction with the NKT cell receptor. Even though the lipidbinding groove of CD1d is widely accommodative of many lipid groups, it is believed that only the sugar structures in a-anomeric orientation are able to stimulate NKT cells [4].…”