Grant: $89,605 - National Institutes of Health - Sep. 14, 2009
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Award Description: Within our cells, there are immune system receptors that capture fragments from viruses (if the cell is infected with a virus, such as influenza), or capture fragments from abnormal proteins if the cell is a cancer cell. These receptors then show these fragments at the outer surface of the cell. Specialized immune system cells can recognize these fragments bound to the receptors at the cell surface and then stop the spread of the virus infection or cancer. For the receptors to bind to the fragments inside cells, several proteins must work together to assist in their assembly. Although several proteins within this assembly group have been identified, the means by which they regulate the binding of these receptors to these fragments are not well understood. Achieving an understanding of how these assembly proteins cause the receptors to bind to the fragments would help in the development of better vaccines and new immunological treatments for viral diseases and cancers. The objective of this project is to better define how one of the proteins involved in controlling the binding of receptors to viral and cancer-specific fragments functions in this process.
Project Description: This supplemental project is to extend the work of one of the originally approved Aims of the parent NIH grant (Aim 1), without duplicating the research described in the parent grant. The basis for our supplemental proposal was our new observation that tapasin has a novel interaction with the major histocompatibility complex (MHC) class I molecule Kd, in that intracellular, folded forms of Kd can remain associated with tapasin. This prolonged tapasin association with folded Kd suggests that Kd may have an unusually high dependency on tapasin. In advance work on this supplemental project, we have been evaluating the role of a tapasin cysteine residue at position 95 in the maturation and surface stability of Kd. To examine the impact of this residue on the maturation of Kd, folded Kd molecules were immunoprecipitated from lysates of tapasin-deficient mouse cells transduced with both Kd and mouse tapasin mutated at position 95 (or wild type tapasin control). Most of the folded Kd molecules assembled in the presence of mouse tapasin cysteine mutants were found to be sensitive to Endo H digestion, indicating that the ability of stable Kd molecules to mature and migrate to the cell surface had been strongly impaired by the substitution of this cysteine in tapasin. Furthermore, we have also determined the effect of this cysteine residue in tapasin on the ability of Kd molecules to remain stably expressed at the cell surface. Folded Kd molecules on mouse tapasin cysteine-mutant cells declined in number more rapidly, relative to Kd molecules on cells expressing wild type mouse tapasin, indicating decreased stability of the folded Kd molecules on the tapasin mutant-expressing cells. Thus, these studies have provided additional understanding of the importance of this cysteine residue to tapasin’s ability to regulate the maturation and stability of the Kd molecule.
Jobs Summary: the project has just started (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Sep. 14, 2009. Help expand these official descriptions using the wiki below.