Conformational Plasticity Revealed by the Cocrystal Structure of NKG2D and Its Class I MHC-like Ligand ULBP3

Abstract

NKG2D is known to trigger the natural killer (NK) cell lysis of various tumor and virally infected cells. In the NKG2D/ULBP3 complex, the structure of ULBP3 resembles the alpha1 and alpha2 domains of classical MHC molecules without a bound peptide. The lack of alpha3 and beta2m domains is compensated by replacing two hydrophobic patches at the underside of the class I MHC-like beta sheet floor with a group of hydrophilic and charged residues in ULBP3. NKG2D binds diagonally across the ULBP3 alpha helices, creating a complementary interface, an asymmetrical subunit orientation, and local conformational adjustments in the receptor. The interface is stabilized primarily by hydrogen bonds and hydrophobic interactions. Unlike the KIR receptors that recognize a conserved HLA region by a lock-and-key mechanism, NKG2D recognizes diverse ligands by an induced-fit mechanism.

Porcine UL16-Binding Protein 1 Expressed on the Surface of Endothelial Cells Triggers Human NK Cytotoxicity through NKG2D

“…Using an algorithm to score potential ligands (29), pULBP1 was predicted to bind human NKG2D using both the crystal structure of human NKG2D/human ULBP3 and human NKG2D/mouse Rae-1␤ interactions as template, whereas pMIC2 was predicted to bind NKG2D only using the structure of human NKG2D/human ULBP3 as template (data not shown). Intriguingly, a previous study showed no binding of pULBP1-Fc to the human NK cell line NKL by flow cytometry, whereas binding to porcine PBMC was revealed (33).…”

“…The latter were identified based on their ability to bind the human CMV glycoprotein UL16. Although these GPI-linked proteins are distantly related to members of the HLA class I family possessing ␣1 and ␣2, but not ␣3 domains (28), they are unable to present peptides (29). In contrast, both MICA and MICB are transmembrane proteins and possess all three ␣ domains.…”

“…Phylogenetic analyses place pULBP1 evolutionarily close to the bovine ULBP-like genes MHCLA1 and MHCLA2. It exhibits 35-52% amino acid identity to human ULBP, including a relatively high level of conservation at positions predicted to make contact with human NKG2D (29). Southern blot analysis suggested that only one pULBP exists in the pig genome, which is in sharp contrast to the much higher number of ULBP genes, at least six, that were described in humans.…”

Cutting Edge: Murine UL16-Binding Protein-Like Transcript 1: A Newly Described Transcript Encoding a High-Affinity Ligand for Murine NKG2D

“…Fig. 1A shows the protein sequence and secondary structural alignment with ULBP3 and RAE1␤ (25,26). It encompasses ␣1-and ␣2-like domains but no ␣3-like domain or predicted GPI transamidation site.…”

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

“…Murine NKG2D recognizes RAE1 family members (RAE1α-ε), H60 (H60a-c), and the murine UL16-binding protein-like transcript 1 (MULT1) (8-10). Remarkably, these NKG2D ligands are related to MHC class I (MHC-I)-like molecules (11,12), and several are targets of MHC-I-like immunoevasins (3). In particular, mouse CMV (MCMV) m152/gp40 (hereafter referred to as "m152") has a dual role, downregulating cell-surface expression of RAE1 family members [but not MULT1 or H60 (13), the targets of MCMV proteins m145 and m155, respectively (14, 15)] as well as host MHC-I molecules (16)(17)(18)(19).…”