Biochemical Characterization of Murine Qa-1
Ramyar, Kasra Xerxes
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Qa-1 is a member of the mouse MHC Ib family with roles in both the adaptive and innate arms of immunity. While it is presumed to be quite similar in structure to the class Ia molecules, Qa-1 has limited polymorphism and only presents a limited repertoire of known peptides. Although Qa-1 is the primary ligand for the Natural Killer cell NKG2/CD94 receptors, Qa-1 restricted CD8+ cytotoxic T cells have also been identified. To better understand the molecular mechanisms of these recognition events and the remarkably short lifetime of the Qa-1/peptide complex, a series of biophysical and biochemical characterizations were made of this molecule. Initial attempts at bacterial expression and in vitro reconstitution of the complex led to the identification of a single residue which drastically destabilizes the complex both in vivo and in vitro. Mutation of this residue results in significant acceleration of Qa-1’s maturation rate as well as increased half-life of the molecule. The ability of this mutant to present peptide to T cells and its interaction with the NKG2 receptor have been investigated. While presentation of the cognate peptide predominantly found in complex with Qa-1 has not been altered, the enhanced cell surface expression and the elongated half-life of the mutant molecule provide insights into the normal physiological role of the wild type molecule as a real-time sensor for immunosurveillance by NK cells and rapid cytotoxic response by the effectors of adaptive immunity.