Lipopeptides: a novel antigen repertoire presented by major histocompatibility complex class I molecules

Abstract

Post-translationally modified peptides, such as those containing either phosphorylated or O-glycosylated serine/threonine residues, may be presented to cytotoxic T lymphocytes (CTLs) by MHC class I molecules. Most of these modified peptides are captured in the MHC class I groove in a similar manner to that for unmodified peptides. N-Myristoylated 5-mer lipopeptides have recently been identified as a novel chemical class of MHC class I-presented antigens. The rhesus classical MHC class I allele, Mamu-B*098, was found to be capable of binding N-myristoylated lipopeptides and presenting them to CTLs. A high-resolution X-ray crystallographic analysis of the Mamu-B*098:lipopeptide complex revealed that the myristic group as well as conserved C-terminal serine residue of the lipopeptide ligand functioned as anchors, whereas the short stretch of three amino acid residues located in the middle of the lipopeptides was only exposed externally with the potential to interact directly with specific T-cell receptors. Therefore, the modes of lipopeptide-ligand interactions with MHC class I and with T-cell receptors are novel and fundamentally distinct from that for MHC class I-presented peptides. Another lipopeptide-presenting MHC class I allele has now been identified, leading us to the prediction that MHC class I molecules may be separated on a functional basis into two groups: one presenting long peptides and the other presenting short lipopeptides. Since the N-myristoylation of viral proteins is often linked to pathogenesis, CTLs capable of sensing N-myristoylation may serve to control pathogenic viruses, raising the possibility for the development of a new type of lipopeptide vaccine.

Keywords: antigen presentation/processing; major histocompatibility complex; structural biology/crystallography.

Figure 1

Phylogenetic tree of Mamu alleles. A phylogenetic tree was constructed by a neighbour‐joining method with bootstrap values of 5000 replications. The α1 and α2 domains of representative alleles belonging to the classical (Mamu‐A and ‐B) and non‐classical (Mamu‐AG, ‐I, ‐E, and ‐F) MHC class I families were analysed. Mamu‐B*098 is shown in red and Mamu alleles known to present peptide antigens are indicated in blue.55

Figure 2

Crystal structure of the Mamu‐B*098:C14nef5 complex. The surface of the antigen‐binding groove of Mamu‐B*098 as well as the bound lipopeptide (yellow stick) are shown. The side chains of some amino acid residues critically interacting with the lipopeptide ligand are also indicated with black lines.

Figure 3

Groove structures for accommodating peptide, lipopeptide, and lipid antigens. Top views of HLA‐B27 (a, PDB code 3B6S), Mamu‐B*098 (b, PDB code 4ZFZ), and CD1a (c, PDB code 1ONQ) molecules are shown in the upper panels. Six pockets (A–F) of HLA‐B27 and Mamu‐B*098 as well as two pockets (A′ and F′) of CD1a molecules are indicated, and bound ligands are shown in yellow sticks. Side views of each complex are illustrated in the corresponding lower panels.