The long-term objective of this research is to understand the biogenesis of peroxisomes in molecular detail.
The aims of this project focus on the machinery for the posttranslational import of proteins into the organelle and on the assembly of the membrane proteins. These studies should provide fundamental information about an intriguing problem in cell biology for which no molecular information is yet available. They may also shed light on several human diseases in which peroxisome assembly is defective. Peroxisomes are nearly ubiquitous in eukaryotic cells and have essential functions including fatty acid catabolism, gluconeogenesis, and plasmalogen biosynthesis. Peroxisomes resemble mitochondria and chloroplasts in that the organelles import posttranslationally proteins that are synthesized on free polyribosomes. Peroxisomes differ in that their proteins generally lack leavable transit peptides, whereas most mitoochondrial and chloroplast proteins are synthesized as larger precursors with topogenic aminoterminal peptides that are removed proteolytically upon import. Our recent experiments implicate an ATPase and a receptor in the import of proteins into peroxisomes. We have identified eight integral membrane proteins of the organelle and raised antisera against them. We plan to look for additional proteins involved in import. We will identify and characterize the ATPase and putative receptor. We plan to clone and sequence the proteins already implicated in the import machinery (and others that may be discovered) and two major membrane proteins that we have already studied (masses of 22 and 69 kDa). The assembly of these proteins will be investigated. We also intend to continue studies on fibroblasts from Zellweger syndrome - our recent data suggests that this disease may be due to a defect in the import machinery.
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