Fungal infections remain a serious cause of morbidity and mortality, especially in immunocompromised patients. Candida albicans is among the most common agents, perhaps because of its normally commensal status. While candidiasis is often superficial in AIDS patients, deeper infections are becoming increasingly common, and are often difficult to treat. In C. albicans, the ALS genes (alpha-Agglutinin Like Sequences) are a large family that mediates substrate adhesion to mammalian cells and self-aggregation. The sequence similarity of Als proteins to the S. cerevisiae sexual cell adhesion protein alpha-agglutinin means that alpha- agglutinin, which is well studied, can serve as a structural and functional prototype for the Als proteins. Additional regions in the Als proteins, but not in alpha-agglutinin, have sequence similarity to S. cerevisiae flocculins, which mediate Ca++-dependent aggregation. We propose that the structure and activities of the S. cerevisiae sexual agglutinins and flocculins can be used as models for the pathogenesis-related ALS proteins from C. albicans. Three dimensional models of the Als protein structure and binding will predict differences in structure and function, and that these differences will relate to the roles of the Als proteins in host-pathogen interaction. In collaboration with Dr. Stephen Klotz: 1. We will determine the binding properties and physical characteristics of three regions of C. albicans Als99p that are predicted to mediate adhesive interactions. 2. We will test the idea that sequences rich in Thr and other beta-branched amino acids are common to the C. albicans ALS gene family model for Als proteins we will determine if the tight binding of the S. cerevisiae agglutinins is mediated by conformational shift in alpha- agglutinin. 4. The binding characteristics of Als99p to its ligands will be investigated following the model resulting from Aim 3. These studies will generate a molecular picture of the structure and function of the Als family of proteins.
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