Abstract
The role of peroxisomal processes in the maintenance of neurons has not been thoroughly investigated. We propose using Caenorhabditis elegans as a model organism for studying the molecular basis underlying neurodegeneration in certain human peroxisomal disorders, e.g. Zellweger syndrome, since the nematode neural network is well characterized and relatively simple in function. Here we have identified C. elegans PEX-5 (C34C6.6) representing the receptor for peroxisomal targeting signal type 1 (PTS1), defective in patients with such disorders. PEX-5 interacted strongly in a two-hybrid assay with Gal4p–SKL, and a screen using PEX-5 identified interaction partners that were predominantly terminated with PTS1 or its variants. A list of C. elegans proteins with similarities to well-characterized yeast β-oxidation enzymes was compiled by homology probing. The possible subcellular localization of these orthologues was predicted using an algorithm based on trafficking signals. Examining the C termini of selected nematode proteins for PTS1 function substantiated predictions made regarding the proteins' peroxisomal location. It is concluded that the eukaryotic PEX5-dependent route for importing PTS1-containing proteins into peroxisomes is conserved in nematodes. C. elegans might emerge as an attractive model system for studying the importance of peroxisomes and affiliated processes in neurodegeneration, and also for studying a β-oxidation process that is potentially compartmentalized in both mitochondria and peroxisomes.
Highlights
The recent completion of the nematode genome sequencing project (Consortium, 1998) promises to provide valuable insights into hitherto uncharacterized biochemical processes in Caenorhabditis elegans that have already been extensively studied in Saccharomyces cerevisiae (Chervitz et al, 1998), such as b-oxidation of fatty acids
The consensus for peroxisomal targeting signal type 1 (PTS1) is no longer precise since non-canonical C-terminal tripeptides can function as PTS1 due to degeneracy and to neighbouring amino acid residues acting as PTS1 enhancers (Elgersma et al, 1996; Lametschwandtner et al, 1998)
To gain a better understanding of whether proteins predicted by computer algorithms to contain PTS1s potentially represented peroxisomal enzymes, the C termini of such candidates could be examined for PTS1 function
Summary
The recent completion of the nematode genome sequencing project (Consortium, 1998) promises to provide valuable insights into hitherto uncharacterized biochemical processes in Caenorhabditis elegans that have already been extensively studied in Saccharomyces cerevisiae (Chervitz et al, 1998), such as b-oxidation of fatty acids. The b-oxidation process occurs in the peroxisomal compartment of all eukaryotic systems tested and, in the mitochondria of mammalian cells (Kunau et al, 1995). Peroxisomes are organelles demarcated by a single membrane that characteristically contain enzymes for oxidative reactions involving molecular oxygen and for metabolizing hydrogen peroxide (de Duve and Baudhuin, 1966). Peroxisomal matrix enzymes, including those involved in b-oxidation, are imported with the help of speci®c targeting signals that interact with cognate receptors. The type 1 peroxisomal targeting signal (PTS1) of some proteins is a carboxyterminal tripeptide that consists of SKL or a variant thereof (Gould et al, 1987; Subramani, 1993), i.e. S/A/C±K/R/H±L (McNew and Goodman, 1996).
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