The peroxisome is a ubiquitous organelle that contains enzymes involved in a variety of important metabolic processes. Although the organelle does not appear to be essential for cell viability, defects in peroxisome assembly cause lethal human genetic disorders in approximately 1/25,000 live births. The overall goal of the research described in this grant application to better understand the molecular basis of these peroxisomal diseases and to obtain a better understanding of the assembly and function of peroxisomes. We have chosen to work in several biological systems, maximizing the advantages of each. We use both mammalian cell lines and yeast for our studies on peroxisome assembly, as well as for our studies on peroxisomal targeting signals and their receptors. Using a functional complementation assay, we will clone the genes responsible for the peroxisome assembly diseases and characterize the encoded gene products. Our collaborators will be able to use these results for clinical purposes, with the aim of aiding diagnosis and/or treatment of these diseases. Two previously identified genes that are required for peroxisome assembly have been shown to encode peroxisomal membrane proteins (PMPs). In an effort to better understand the biogenesis of PMPs and other important peroxisomal proteins, we will identify and characterize new peroxisomal targeting signals (PTSs) that direct proteins to and into the organelle, focussing on the signals that direct proteins to the peroxisomal membrane. We also study peroxisome assembly in yeast, making use of the efficient molecular genetic manipulations that are possible in this organism. Peroxisome-deficient mutants in 13 complementation groups have been isolated and we are using these mutants to identify the genes and characterize the gene products that are required for peroxisome assembly. The integration of these projects in our laboratory makes for a very stimulating research environment, and the location of our laboratory within the one of the largest centers for peroxisome research provides an unparalleled level of interaction and collaboration.
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