Immunophilins in the Yeast Saccharomyces cerevisiae: A Different Spin on Proline Rotamases

The clinically used immunosuppressant compounds-FK506, rapamycin, and cyclophilin A-are all natural products that were originally detected because of their antifungal action, not because of their fortuitous effects on the human immune system. Genetic and biochemical approaches have been used to identify binding proteins that serve as the receptors for these antibiotics in cells of the budding yeast Saccharomyces cerevisiae. Three FK506/rapamycin-binding proteins (FKBPs) and six cyclosporin-A-binding proteins (cyclophilins) have been characterized in some detail, but there is evidence that additional members of both families exist in this organism. Cloning of the corresponding genes has shown that the yeast gene products are strikingly similar to their mammalian counterparts and possess peptidylprolyl-cis, trans-isomerase (proline rotamase) activity in vitro. Genetic analysis in yeast has confirmed, and significantly extended, complementary research in animal cell systems that has shed light on the roles that the FKBPs and the cyclophilins play in the mechanism of action of the immunosuppressant drugs. The application of genetic methods in yeast is also beginning to provide additional insights into the function of these proteins in normal cell physiology.