Structure of UL18, a peptide-binding viral MHC mimic, bound to a host inhibitory receptor

Abstract

UL18 is a human cytomegalovirus class I MHC (MHCI) homolog that binds the host inhibitory receptor LIR-1 and the only known viral MHC homolog that presents peptides. The 2.2-Å structure of a LIR-1/UL18/peptide complex reveals increased contacts and optimal surface complementarity in the LIR-1/UL18 interface compared with LIR/MHCI interfaces, resulting in a >1,000-fold higher affinity. Despite sharing only Ϸ25% sequence identity, UL18's structure and peptide binding are surprisingly similar to host MHCI. The crystal structure suggests that most of the UL18 surface, except where LIR-1 and the host-derived light chain bind, is covered by carbohydrates attached to 13 potential N-glycosylation sites, thereby preventing access to bound peptide and association with most MHCI-binding proteins. The LIR-1/UL18 structure demonstrates how a viral protein evolves from its host ancestor to impede unwanted interactions while preserving and improving its receptor-binding site.cytomegalovirus ͉ immune evasion ͉ LIR-1 ͉ x-ray crystallography H uman cytomegalovirus (HCMV) is prevalent among all human populations, infecting 70-90% of adults (1). HCMV infection is usually asymptomatic in immunocompetent individuals, but the virus causes a latent infection that can be reactivated during immune suppression. To maintain persistence in the presence of a primed immune system, HCMV has developed mechanisms to subvert the host immune response (2). One strategy is to downregulate cell surface expression of host class I MHC molecules, thereby allowing HCMV-infected cells to avoid recognition by virus-specific cytotoxic T cells. However, cells that lack surface class I MHC molecules are susceptible to lysis by natural killer (NK) cells (3). NK cells express both activating receptors and inhibitory receptors, many of which recognize class I MHC molecules (4). Stimulation of the activating receptors leads to lysis of target cells when expression of class I MHC proteins is down-regulated (5); however, clinical isolates of HCMV can evade NK lysis (6) by down-regulation (7) or inhibition (8) of the activating ligands for NK cells; up-regulation of HLA-E (9), which binds the NK cell inhibitory receptor NKG2A/CD94; and potentially through the expression of two virally encoded class I MHC homologs, UL142 (10) and UL18 (11).UL18 is a heavily glycosylated transmembrane protein that shares Ϸ25% sequence identity with class I MHC molecules (11). It associates with the class I MHC light chain, ␤2-microglobulin (␤2m) (12), and with endogenous peptides derived from cytoplasmic proteins that resemble those bound to host class I proteins (13). Peptide binding renders UL18 unique among viral MHC homologs and unusual among host MHC homologs. The role of UL18 in NK cell recognition is controversial; it has been reported to inhibit NK-cell-mediated lysis in some experimental conditions but not others (14).The only host receptor identified for UL18 is LIR-1 (15) (also known as ILT2, CD85j, or LILRB1) (16). LIR-1 is expressed on most or all monocytes, dendritic and...

Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion

“…In particular, the α2 helix domain residues of RAE1γ, including Lys154, Tyr155, and Glu159, form an important contact site for both m152 and NKG2D. (33), that of the MHC-I-like UL18 with the Ig-like LIR-1 (34), and that of the Ig-like UL16 with the MHC-I-like hNKG2D ligand MICB (29). In all these complexes, the viral molecule exploits a different aspect of the host cell's ligand for interaction.…”

Cis association of leukocyte Ig‐like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18

“…LIR-1 is also targeted by a virally encoded MHC-I homologue known as UL18 [10], which shares approximately 25% amino acid sequence identity with MHC-I and associates with human β 2 -microglobulin [11,12]. UL18 binds to LIR-1 with more than 1000-fold greater affinity than MHC-I molecules [7,13,14] and has been shown to mediate suppression of LIR-1 + NK cells in vitro [15]. Studies of LIR-1 function to date have primarily focused on the interaction of the receptor with its ligand in trans, such as inhibition of NK or T cells through recognition of a ligand expressed on a target cell or APC [16][17][18][19][20][21].…”

“…LIR-1 is also targeted by a virally encoded MHC-I homologue known as UL18 [10], which shares approximately 25% amino acid sequence identity with MHC-I and associates with human β 2 -microglobulin [11,12]. UL18 binds to LIR-1 with more than 1000-fold greater affinity than MHC-I molecules [7,13,14] and has been shown to mediate suppression of LIR-1 + NK cells in vitro [15].…”

Structural immunology and crystallography help immunologists see the immune system in action: How T and NK cells touch their ligands

“…Current available crystal structures of LILR B1/B2/A2/A5 only include their D1 and D2 domains (D1D2) (55,56,(66)(67)(68)(69). Though the instability and precipitation of wild-type LILRA2 (ILT1/LIR-7/CD85h) D1D2 has been documented (70), a cysteine-introduced mutation (R142C) was developed to form a disulfide bond with the spare Cys132, which stabilizes the protein and enhances the recombinant production of the LILRA2 D1D2 protein (71).…”