Wednesday, May 1, 2024
5/1/2024
DESCRIPTION (provided by applicant): Immunological Significance: NKG2D is an activating receptor found on several types of immune cells. Stressed cells express cell-surface proteins such as MIC-A that bind NKG2D, initiating an important cytotoxic immune response. A constitutively stabilized MIC-A, resulting in a more stable NKG2D--MIC-A interaction, would be an improved immunological staining reagent and a potential therapeutic agent that could downregulate natural killer cell activation in graft-vs.-host disease (GVHD). Hypothesis: Crystal structures have revealed that a disordered portion of the MIC-A surface folds upon NKG2D binding. The NKG2D--MIC-A interaction exhibits unusual thermodynamic characteristics, including a high heat capacity, that are hypothesized to be related to this structural transition. Method: Undergraduate student researchers will test this hypothesis by selecting a strategy to mutate MIC-A according to the analysis of a computational algorithm, with the ultimate aim to produce a constitutively ordered MIC-A. We will then study the impact of these mutations on NKG2D--MIC-A stability, entropy, enthalpy, heat capacity, and kinetics using a surface plasmon resonance technique previously demonstrated for both TCR-MHC and NKG2D-ligand interactions. A more stable MIC-A loop region is predicted to result in lower heat capacity for the NKG2DuMIC -A interaction, but should not markedly affect dissociation rate. Teaching Aims: Students will learn standard protein manipulation and production techniques in the course of discovering new relationships between protein-protein interface structure, design, and thermodynamics.
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