The PRS gene family - a means of linking primary metabolism and cell signalling?

Saccharomyces cerevisiae as well as contributing to bread, wine, beer and Marmite (!) has become a pioneer organism for functional genomics, systems biology and is a model eukaryote for the study of human disease. The ancestral S. cerevisiae genome has undergone a whole genome duplication providing, as a result of natural selection, the opportunity for diversification and linkage of apparently diverse aspects of yeast physiology. I will present evidence for this taking as an example the gene family capable of encoding PRPP (5-phospho-1(α)-pyrophosphate) syntethase. PRPP is a key metabolite that plays a central role in many life processes, such as in the de novo and salvage biosyntheses of purine, pyrimidine and pyridine nucleotides. The genome of S. cerevisiae contains five highly homologous paralogous genes, designated PRS1-PRS5, encoding polypeptides which exist in the cell as two complexes, one of which is a heterodimer, Prs1/Prs3 and the other, a heterotrimer, Prs2/Prs4/Prs5. Physical evidence for the genetically-defined Prs1/Prs3 complex was obtained showing that in the absence of Prs3, Prs1 is unstable. Prs1 and Prs5 are distinguished by the presence of one and two NHRs (Non-Homologous Regions), respectively. It is not surprising that these insertions are not gratuitous but serve as a link to elements of the cell wall integrity (CWI) signalling pathway. Therefore, in addition to supplying the cell with PRPP, Prs polypeptides are required for the maintenance of CWI: NHR1-1 of Prs1 interacts with the MAPK Slt2, a component of the CWI pathway and the phosphorylation status of Prs5 impinges on CWI as demonstrated by changes in the phosphorylation pattern of Slt2 and in the expression of targets of the CWI pathway.
The human genome contains three PRS genes, two of which are X-linked. Mutations in human PRS genes are associated with several neuropathies, Arts syndrome and Charcot-Marie-Tooth disease. The high sequence similarity of the human PRS genes and the S. cerevisiae PRS1 gene has allowed the creation of genocopies in yeast of the mutations associated with the above-mentioned human neuropathies thereby providing the opportunity to examine the influence of such mutations on yeast physiology and metabolism.
The seminar will give insight into how the yeast PRPP-synthesizing complexes and their cooperation with the CWI pathway have been investigated at the molecular level.