Understanding Membrane Transport and Intercellular Communication

Undergraduate students have participated keenly in all aspects of the research program of our laboratory. Our team has succeeded in cloning and sequencing peptide transport genes from a number of organisms including the yeast Saccharomyces cerevisiae, the fungal pathogen Candida albicans, and the plant Arabidopsis thaliana. Analysis of the proteins encoded by these genes indicates that they represent members of a new family of membrane transport proteins. We have also cloned a second gene involved in peptide transport in S. cerevisiae. Not only is this second gene involved in controlling the transcription of the gene encoding the membrane transport protein, but it also is implicated in the ubiquitin-mediated proteolytic pathway. The physiological connection between peptide transport and the ubiquitin pathway is yet to be unravelled, but the linkage may be representative of global controls of metabolism through seemingly disparate, interlocking pathways. We believe this research on the molecular biology of peptide transport will aid in drug design and delivery because the rational strategy for peptide-based drugs must include knowledge concerning passage of such molecules across biological membranes.

Undergraduates have participated in our research on peptide pheromones as well. An understanding of the initial event of pheromone action - the interaction of pheromone with its receptor - is necessary for understanding intercellular communication and signal transduction. Furthermore, this knowledge should provide information useful in designing antagonists and superactive agonists for therapy of human endocrinological disorders since pheromones are structurally and functionally equivalent to hormones. We have synthesized and analyzed novel analogs of the Saccharomyces cerevisiae mating pheromones, (-factor and a-factor, by a variety of techniques combining chemistry and molecular biology. Some of these new analogs represent the first S. cerevisiae pheromones with greater activity than the naturally occurring peptides. Furthermore, we have found that a single peptide substrate can be covalently modified in a number of ways. This latter finding may have important implications in the development of anticancer agents targeted against modified proteins encountered in many human cancers. In the future, I trust that my laboratory can continue to interest undergraduate students in a research experience. The opportunity to explore an interesting biological problem in association with postdoctoral fellows and graduate students and in a supportive environment provides a terrific learning experience that is usually the highlight of an undergraduate's academic life at the University.