How proteins penetrate peroxisomes

Three decades after the unobtrusive debut of the peroxisome as a distinct subcellular organelle, biologists are paying attention to the special bag of tricks eukaryotic cells use to entice peroxisomal proteins from their site of synthesis in the cytosol to the peroxisome. In this minireview, we highlight some of the recent findings that have emerged, emphasize their significance, and contrast them with aspects of protein import into other subcellular destinations. Peroxisomal Targeting Signals The Beginning, the Middle, and the End Genetic and biochemical evidence has underscored the conservation of peroxisomal targeting signals (PTSs) from yeast to humans and led to the elucidation of at least two pathways for the transport of proteins to the peroxisome matrix (lumen). Each of these pathways is dependent on the molecular recognition of a specific PTS by its cognate receptor, which then hands off the protein to a putative translocation machinery housed in the peroxisome membrane. PTSl is a conserved C-terminal tripeptide (SKL or a variant) that constitutes the major targeting signal for proteins destined for the peroxisome matrix. In contrast, PTS2 is a conserved N-terminal nonapeptide (R/K)(L/V/I) (X)5(H/Q)(L/A) used by a smaller subset of peroxisomal matrix proteins. Other internally located PTSs have been described but remain poorly characterized (Purdue and Lazarow, 1994). Peroxisomal membrane proteins do not possess either PTSl or PTS2 sequences but are endowed instead with PTSs that have been defined only as fairly large internal segments of peroxisomal membrane proteins (Purdue and Lazarow, 1994). Despite the fact that all these PTSs are known to be necessary and sufficient for targeting to peroxisomes, a novel twist (addressed later) is the recent discovery that polypeptide chains devoid of a PTS can hitch a ride into peroxisomes by association with subunits that contain a PTS (Glover et al., 1994; McNew and Goodman, 1994). Omnipresent PTS Receptors Yeast and human cells selectively deficient in the PTS1 or PTS2 import pathway (or both) have been instrumental in the identification of PTS receptors. The earliest mutant discovered to be selectively compromised in the PTSl pathway alone was the pas8 mutant of Pichia pastoris. The protein, Pas8p, is tightly associated with the cytosolic face of the peroxisome membrane and is the PTSl receptor (PTSl R) (Terlecky et al., 1995; Figure 1). Minireview