The aims of the project are two-fold in focus. First, the project outlines approaches which extend current research in progress designed to address the role beta-2 macroglobulin (B2m) plays in class I structure and function. Secondly, the project outlines approaches to identify mechanism(s) leading to null B2m/class I expression seen for an established breast cancer cell line, MDA- MB-157. Previous result have demonstrated that following human B2m exchange, an Ltk- transfectant expressing H-2Ld exhibits a marked increase in 34-1-2 antibody cross- reactivity. Subsequent studies substantiated that human B2m induced 34-1-2 cross-reactivity by imparting a conformational change within the alpha-1 helical region of class I. Approaches presented herein will focus on clearly discerning B2m specific amino acid positions involved in imparting structural influence over the alpha-1 helica region, a region important in class I/peptide interaction. In addition, the level to which class I molecules are conformationally flexible and hence susceptible to structural perturbations induced by B2m will also be investigated. Other previous results have also demonstrated that B2m mutations are responsible for null class I expression for a breast cancer cell line, MDA-MB-157. Identification of novel mutational events that have occurred within B2m genes isolated from cancer cells, could provide insight into; 1) the structure/function relationship of B2m and class I, and 2) mechanisms involved in B2m and class I gene expression. Given that the project will focus on clarifying the role B2m plays in class I function, ramifications for the role class I molecules play in immune system surveillance and regulation will so be addressed.
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