Crystal structure of NKp30 and identification of ligand binding site through peptide mapping and blocking antibodies (94.12)

Abstract

Abstract Natural Killer cells are a group of innate immune cells which carry out continuous surveillance for the presence of virally infected or cancerous cells. These lymphocytes are activated without any prior immune priming and elicit their effects via a combination of both activating and inhibitory receptors ensuring a highly sensitive mechanism which allows the differentiation between healthy and transformed cells. NKp30 is known to be the dominant activating receptor responsible for the destruction of a number of specific tumor cell types. In addition, NKp30 has been shown to cause the activation and expansion of resting NK cells upon interaction with dendritic cells and in addition to cause the death of immature dendritic cells (imDCs). The precise mechanism of how NKp30 interacts with virus-infected, cancerous cells and imDCs initiating NK cell killing is an intriguing question and to date, a number of NKp30 interacting molecules have been proposed. These molecules are quite diverse, ranging from Heparan sulphate to a plasmodium falciparum molecule and most recently a B7 homolog protein. How NKp30 recognizes these diverse molecules is to date unknown. In order to address this question we have determined the crystal structure of the extracellular domain of human NKp30. In an attempt to understand how NKp30 binds diverse ligands, we have identified a putative ligand binding region on the surface of NKp30 through peptide mapping and competition with blocking antibodies.