title: NKG2D and Related Immunoreceptors.
abstract: NK cells are crucial components of the innate immune system, capable of directly eliminating infected or tumorigenic cells and regulating down-stream adaptive immune responses. Unlike T cells, where the key recognition event driving activation is mediated by the unique T cell receptor (TCR) expressed on a given cell, NK cells express multiple activating and inhibitory cell-surface receptors (NKRs), often with overlapping ligand specificities. NKRs display two ectodomain structural homologies, either immunoglobulin- or C-type lectin-like (CTLD). The CTLD immunoreceptor NKG2D is found on NK cells but is also widely expressed on T cells and other immune system cells, providing stimulatory or co-stimulatory signals. NKG2D drives target cell killing following engagement of diverse, conditionally expressed MHC class I-like protein ligands whose expression can signal cellular distress due to infection or transformation. The symmetric, homodimeric receptor interacts with its asymmetric, monomeric ligands in similar 2:1 complexes, with an equivalent surface on each NKG2D monomer binding extensively and intimately to distinct, structurally divergent surfaces on the ligands. Thus, NKG2D ligand-binding site recognition is highly degenerate, further demonstrated by NKG2D's ability to simultaneously accommodate multiple non-conservative allelic or isoform substitutions in the ligands. In TCRs, "induced-fit" recognition explains cross-reactivity, but structural, computational, thermodynamic and kinetic analyses of multiple NKG2D-ligand pairs show that rather than classical "induced-fit" binding, NKG2D degeneracy is achieved using distinct interaction mechanisms at each rigid interface: recognition degeneracy by "rigid adaptation." While likely forming similar complexes with their ligand (HLA-E), other NKG2x NKR family members do not require such recognition degeneracy.
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Roland K
authors.initials: RK
authors.lastname: Strong
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: McFarland
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D055655:NK Cell Lectin-Like Receptor Subfamily K; D010802:Phylogeny; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell