The fungal cell wall plays a critical role in protecting cells from osmotic stress and, in conjunction with the actin cytoskeleton, in regulating cell shape as a function of cell growth. In many fungal species growth is polarized during the formation of buds, mating projections and hyphae. Components found in the cell wall also regulate cell-cell adhesion reactions such as flocculation during vegetative growth, sexual agglutination and pathogen-host cell adhesion. These processes are crucial to the life cycles of many fungi pathogenic to humans including Candida species, Cryptococcus neoformans, Aspergillus fumigatus and Histoplasma capsulatum. While many key adhesion molecules responsible for cell-cell adhesion have been identified, little is presently known concerning the factors that regulate the localization, trafficking and activity within the cell wall of these glycoproteins which play key roles in pathogenesis. This proposal aims to further elucidate the structure and function of conserved WCPL and CX4C domains found in a super family of cell wall Mann proteins that are present in both S. cerevisiae and C. albicans and involved in their differentiation. The genetically tractable system of cell adhesion during mating in S. cerevisiae will be used to study the domain organization, cell wall localization and mechanisms regulating activity of a model cell wall protein, Agalp, which is a member of the super family. These studies will use biochemical and genetic methods to investigate the possibility that the WCPUCX4C domains mediate post-secretory traffic of the protein within or at the surface of the fungal cell wall. A novel approach designed to develop peptide reagents with the potential to act as specific inhibitors of the fungal adhesins Aga2p and Hwpl p and/or as structural platforms for antifungal drug development and delivery will be explored. We expect these studies to add to our understanding of fungal cell wall Mann protein modification, localization and function; such information is likely to be useful to the future design and targeting of anti-fungal agents.