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The Budding Yeast Pex5p Receptor Directs Fox2p and Cta1p Into

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The Budding Yeast Pex5p Receptor Directs Fox2p and Cta1p Into © 2018. Published by The Company of Biologists Ltd | Journal of Cell Science (2018) 131, jcs216986. doi:10.1242/jcs.216986 RESEARCH ARTICLE The budding yeast Pex5p receptor directs Fox2p and Cta1p into peroxisomes via its N-terminal region near the FxxxW domain Łukasz Rymer*, Błażej Kempiński*, Anna Chełstowska and Marek Skoneczny‡ ABSTRACT the cell. A comprehensive account of peroxisome biogenesis and The import of most of peroxisomal proteins into the lumen of their functions can be found in the recent special issue of Biochimica et target organelle is driven by C-terminal (PTS1) or N-terminal (PTS2) Biophysica Acta (2016, vol. 1863, pp. 787-1069). When compared signals recognized by the Pex5p or Pex7p receptors, respectively. with the proteomes of other organelles, the peroxisomal proteome However, some proteins in budding yeast, such as acyl-CoA oxidase is relatively small. Currently, the number of known peroxisomal (AOx) and carnitine acetyltransferase (Cat2p), are imported into proteins in humans is 101, while that in budding yeast peroxisomes via an alternative route that does not rely on known (Saccharomyces cerevisiae Meyen ex E.C. Hansen) is 75 (http:// PTS signals and involves the Pex5p receptor N-terminal region. Here, www.peroxisomedb.org/, accessed 17 July, 2018) (Schlüter et al., we show that two other budding yeast peroxisomal proteins, a 2010). Of those proteins, only a subset is localized in the multifunctional enzyme from the β-oxidation pathway (Fox2p) and peroxisomal lumen; however, the mechanisms for the import of catalase A (Cta1p), both of which contain PTS1, can be imported these few proteins into peroxisomes are surprisingly diverse. independently of this signal. The I264K amino acid substitution in Peroxisomal matrix proteins are imported post-translationally, and Pex5p adjacent to its FxxxW diaromatic motif, previously shown to the specificity of transport depends on the peroxisome-specific abolish the import of AOx and Cat2p into peroxisomes, also affects targeting signal encoded in the protein sequence. Thus far, two such Fox2p and Cta1p import. Moreover, we demonstrate that Pex9p, a signals are known and have been well-characterized: peroxisomal newly discovered paralog of Pex5p that was recently implicated in the targeting signal 1 (PTS1) and peroxisomal targeting signal 2 (PTS2) import of malate synthases in budding yeast, also exhibits weak (Girzalsky et al., 2010). receptor activity towards Fox2p and Cta1p. These findings indicate The PTS1 targeting signal was established as a tripeptide located at the need to re-evaluate the peroxisomal import paradigm. the extreme C-terminus of proteins (Gould et al., 1989). While an SKL sequence appears to be the most typical, permutation analysis This article has an associated First Person interview with the first led to the formulation of a more flexible rule for the PTS1 signal: author of the paper. (S/A/C)-(K/H/R)-(L) (Swinkels et al., 1992). The comparison of many PTS1 sequences in mammals, plants, protozoa and yeast KEY WORDS: PTS3, Dual-function receptor, Peroxisome biogenesis, allowed the generalization of the PTS1 composition as follows: Peroxisome matrix proteins, Pex9p (small)-(basic)-(large non-polar) amino acids. In silico analysis generalized the consensus even further (Nötzel et al., 2016). The INTRODUCTION tripeptide PTS1-like sequence is present in the majority of Peroxisomes are small vesicular organelles that are present in almost peroxisomal matrix proteins and is necessary and usually sufficient all eukaryotic cells. They are surrounded by a single membrane to direct reporter proteins to peroxisomes. Interestingly, however, and contain diverse sets of enzymes that are involved in several some PTS1 variants are not active in a heterologous context, although metabolic pathways, including fatty acid β-oxidation and lipid they function in the proteins in which they naturally occur. This biosynthesis. Peroxisomes are characterized by the presence of a behavior implies that some additional information may be needed for number of oxidases that produce hydrogen peroxide, which is the import of these proteins. Therefore, the complete PTS1 signal decomposed by catalase (Tolbert, 1981). ensuring the proper recognition of peroxisomal proteins has been The comparison of peroxisomal protein contents in different proposed to include up to nine amino acid residues preceding the tissues and species demonstrates that some tissues and species C-terminal tripeptide (Brocard and Hartig, 2006). lack peroxisomal proteins that are present in others, which clearly A much smaller group of peroxisomal matrix proteins uses a reflects the ability of peroxisomes to adjust to specific metabolic PTS2 signal consisting of nine amino acids with the consensus functions. Even within evolutionarily related groups, such as sequence (R/K)-(L/I/V)-X5-(H/Q)-(L/A/F) located within the first mammals, peroxisome diversity is observed (Islinger et al., 2010). 40 N-terminal amino acids of the protein (Lazarow, 2006). To date, Moreover, the peroxisomal proteome may be modified to adapt to only two proteins with functional PTS2 sequences have been changes in environmental conditions and the metabolic state of identified in S. cerevisiae, 3-ketoacyl-CoA thiolase (Fox3p/Pot1p) (Erdmann, 1994) and glycerol-3-phosphate dehydrogenase (Gpd1p) (Jung et al., 2010). Curiously, the import of the Department of Genetics, Institute of Biochemistry and Biophysics, Polish Academy nicotinamidase Pnc1p into peroxisomes also depends on the of Sciences, Pawińskiego 5A, 02-106 Warszawa, Poland. *These authors contributed equally to this work PTS2 signal, but it relies on the signal in Gpd1p via a piggy-back import mechanism (Effelsberg et al., 2015; Kumar et al., 2016; ‡ Author for correspondence ([email protected]) Saryi et al., 2017), another feature that is characteristic of M.S., 0000-0001-9922-2276 peroxisome biogenesis. Two well-known peroxisomal proteins in S. cerevisiae function Received 18 February 2018; Accepted 7 August 2018 as import receptors: Pex5p with tetratricopeptide repeat (TPR) Journal of Cell Science 1 RESEARCH ARTICLE Journal of Cell Science (2018) 131, jcs216986. doi:10.1242/jcs.216986 domains and Pex7p with WD-40 domains, which recognize PTS1 the PTS1 signal on its C-terminus, although the signal itself was and PTS2 signals, respectively. While Pex5p can function as an proven to be fully functional in a heterologous context (Elgersma autonomous receptor, Pex7p requires the co-receptors Pex18p and et al., 1995). These results were later corroborated by narrowing Pex21p (Purdue et al., 1998), which stabilize and target the down the region in the Pex5p polypeptide that is important for peroxisomal membrane cargo-bound Pex7p (Stein et al., 2002). the import of these two proteins to the 250-270 aa fragment Recently, another yeast protein, which for two decades was a encompassing the diaromatic motif FxxxW. Individual residues known paralog of Pex5p with no assigned function, was shown to indispensable for AOx and/or Cat2p recognition were identified participate in the import of a subset of PTS1-dependent peroxisomal within this motif and at neighboring positions (Klein et al., 2002). matrix proteins and was named Pex9p (Effelsberg et al., 2016; Therefore, the two budding yeast proteins AOx and Cat2p appeared Yifrach et al., 2016). However, its role in the peroxisomal import to utilize an alternative peroxisomal import pathway, which was machinery is still not fully understood. tentatively called the PTS3 route, even though its components The receptor-assisted translocation of proteins into the remain unknown to date. In particular, we do not know the PTS3 peroxisomal lumen occurs via a transient pore that is formed in signal itself – i.e. the consensus sequence – if one exists, of the the peroxisomal membrane by Pex5p and Pex14p peroxins and, amino acids that direct AOx and Cat2p into peroxisomes. depending on the cargo size, can be as wide as 9 nm (Meinecke Another question that remains is the number of proteins that et al., 2010). This mechanism distinguishes peroxisomes from other actually utilize this route. Are AOx and Cat2p the only budding cellular organelles, and the temporary nature of the import pores yeast proteins that are imported into peroxisomes via the explains past contradictory findings demonstrating that the hypothetical PTS3 route? Most peroxisomal matrix proteins peroxisomal membrane is able to maintain a pH gradient contain a PTS1 or PTS1-like tripeptide at their C-terminus. (Waterham et al., 1990) but is permeable to bulky particles Notably, however, many of them were assigned to the PTS1- (Walton et al., 1995). This unique mechanism allows the dependent import route solely because of the presence of the PTS1 peroxisome to internalize proteins in their native folded signal. The dependence of their import on this signal had been conformation and oligomeric protein complexes. As a implied but not proven directly. Therefore, a reasonable question consequence, proteins that lack their own PTS signal can be is whether the PTS1 signal is necessary and sufficient to drive imported into peroxisomes in association with PTS-containing these proteins into peroxisomes in all cases or if it is sometimes proteins via the piggy-back mechanism mentioned above. dispensable, as in the case of Cat2p. Finally, there are proteins that Curiously, two distinct types of membrane pores are created in the are functionally associated with peroxisomes but not shown to be peroxisomal
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