title: Crystal structure of human natural cytotoxicity receptor NKp30 and identification of its ligand binding site.
abstract: Natural killer (NK) cells are a group of innate immune cells that carry out continuous surveillance for the presence of virally infected or cancerous cells. The natural cytotoxicity receptor (NCR) NKp30 is critical for the elimination of a large group of tumor cell types. Although several ligands have been proposed for NKp30, the lack of a conserved structural feature among these ligands and their uncertain physiological relevance has contributed to confusion in the field and hampered a full understanding of the receptor. To gain insights into NKp30 ligand recognition, we have determined the crystal structure of the extracellular domain of human NKp30. The structure displays an I-type Ig-like fold structurally distinct from the other natural cytotoxicity receptors NKp44 and NKp46. Using cytolytic killing assays against a range of tumor cell lines and subsequent peptide epitope mapping of a NKp30 blocking antibody, we have identified a critical ligand binding region on NKp30 involving its F strand. Using different solution binding studies, we show that the N-terminal domain of B7-H6 is sufficient for NKp30 recognition. Mutations on NKp30 further confirm that residues in the vicinity of the F strand, including part of the C strand and the CD loop, affect binding to B7-H6. The structural comparison of NKp30 with CD28 family receptor and ligand complexes also supports the identified ligand binding site. This study provides insights into NKp30 ligand recognition and a framework for a potential family of unidentified ligands.
authors: Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors: M Gordon
authors: MG
authors: Joyce
authors: Paul
authors: P
authors: Tran
authors: Marina A
authors: MA
authors: Zhuravleva
authors: Jessica
authors: J
authors: Jaw
authors: Marco
authors: M
authors: Colonna
authors: Peter D
authors: PD
authors: Sun
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000737:chemistry* / Q000235:genetics; D017434:Protein Structure, Tertiary
chemical_list: D008024:Ligands; C431710:NCR3 protein, human; D055628:Natural Cytotoxicity Triggering Receptor 3