CAAX Processing and Yeast a-Factor Biogenesis

The Saccharomyces cerevisiae mating pheromone a-factor is an extracellular signaling peptide that is farnesylated and carboxylmethylated. While these posttranslational modifications were first discovered for pheromones secreted by several obscure basidiomycetous fungi, the sophisticated genetic tools available in the model organism S. cerevisiae provided the basis for rapid advancement in the prenylation field. Mature a-factor is derived from a precursor that undergoes CAAX processing (farnesylation, endoproteolysis or "AAXing" of the CAAX motif, followed by carboxylmethylation). Yeast a-factor has been a valuable model for the genetic identification of the CAAX-processing enzymes, comprising in yeast the farnesyltransferase (Ram1p/Ram2p), the AAXing endoproteases (Ste24p and Rce1p), and the carboxylmethyltransferase (Ste14p). In this chapter, we review the discovery of the CAAX-processing machinery and also describe the subsequent steps of a-factor biogenesis, including N-terminal proteolytic processing events (carried out by Ste24p and Axl1p) and a nonclassical export mechanism mediated by the ABC transporter Ste6p. We also discuss how yeast a-factor studies have provided insights into two important biological phenomena in metazoan cells: first, the maturation of the mammalian nuclear scaffold protein lamin A, for which persistent prenylation results in the premature aging disease progeria and related progeroid disorders; second, a secreted molecule involved in Drosophila germ cell migration, whose biogenesis, like that of a-factor, requires CAAX processing and a Ste6p-like transporter. Importantly, these examples suggest that a-factor biogenesis studies will continue to have an impact on our understanding of disease and development in higher organisms.