Abstract
NK cells use surface NK receptors to discriminate self from non-self. The NK receptor ligand-binding domain (NKD) has been considered the sole regulator of ligand binding. Using a prototypic murine NK receptor, Ly49A, we show that the membrane proximal nonligand binding ecto-domain (the stalk region) is critical to ligand binding and signaling. The stalk region is required for receptor binding to ligand on target cells (trans interaction), but is dispensable for receptor binding to ligand on the same cell (cis interaction). Also, signaling in a trans manner depends on the stalk region mediating the formation of the immunological synapse. Thus, our data modeling receptor function at the cellular level reveal an essential role for the stalk region as a specific mediator of receptor signal integration, by which NKD-ligand interactions at the interface initiate and deliver information to the spatially separated cytoplasmic domain.