Peroxisomal protein import

Stable Identifier
Homo sapiens
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Peroxisomes are small cellular organelles that are bounded by a single membrane and contain variable compositions of proteins depending on cell type. Peroxisomes function in oxidation of fatty acids, detoxification of glyoxylate, and synthesis of plasmalogens, glycerophospholipids containing an alcohol with a vinyl-ether bond (reviewed in Lohdi and Semenkovich 2014). All of the approximately 46 proteins contained in peroxisomal matrix are imported from the cytosol by a unique mechanism that does not require the imported proteins to be unfolded as they cross the membrane (Walton et al. 1995, reviewed in Ma et al. 2011, Fujiki et al. 2014, Baker et al. 2016, Dias et al 2016, Emmanoulidis et al. 2016, Erdmann 2016, Francisco et al. 2017). The incompletely characterized process appears to involve the transport of the proteins through a variably sized pore in the membrane comprising at least PEX5 and PEX14 (inferred from the yeast homologs in Meinecke et al. 2010, the yeast pore is reviewed in Meinecke et al. 2016). Oligomeric proteins are also observed to cross the peroxisomal membrane (Otera and Fujiki 2012) but their transport appears to be less efficient than monomeric proteins (Freitas et al. 2011, inferred from mouse homologs in Freitas et al. 2015, reviewed in Dias et al. 2016).
In the cytosol, receptor proteins, PEX5 and PEX7, bind to specific sequence motifs in cargo proteins (Dodt et al. 1995, Wiemer et al. 1995, Braverman et al. 1997). The long and short isoforms of PEX5 (PEX5L and PEX5S) bind peroxisome targeting sequence 1 (PTS1, originally identified in firefly luciferase by Gould et al. 1989) found on most peroxisomal matrix proteins; PEX7 binds PTS2 (originally identified in rat 3-ketoacyl-CoA thiolase by Swinkels et al. 1991) found on 3 imported proteins thus far in humans. The long isoform of PEX5, PEX5L, then binds the PEX7:cargo protein complex (Braverman et al. 1998, Otera et al. 2000). PEX5S,L bound to a cargo protein or PEX5L bound to PEX7:cargo protein then interacts with a complex comprising PEX13, PEX14, PEX2, PEX10, and PEX12 at the peroxisomal membrane (Gould et al. 1996, Fransen et al. 1998, inferred from rat homologs in Reguenga et al. 2001).
The ensuing step in which the cargo protein is translocated across the membrane is not completely understood. During translocation, PEX5 and PEX7 become inserted into the membrane (Wiemer et al. 1995, Dodt et al. 1995, Oliveira et al. 2003) and expose a portion of their polypeptide chains to the organellar matrix (Rodrigues et al. 2015). One current model envisages PEX5 as a plunger that inserts into a transmembrane barrel formed by PEX14, PEX13, PEX2, PEX10, and PEX12 (the Docking-Translocation Module) (Francisco et al. 2017).
After delivering cargo to the matrix, PEX5 and PEX7 are recycled back to the cytosol by a process requiring mono-ubiquitination of PEX5 and ATP hydrolysis (Imanaka et al. 1987, Thoms and Erdmann 2006, Carvalho et al. 2007). PEX7 is not ubiquitinated but its recycling requires PEX5 mono-ubiquitination. A subcomplex of the Docking-Translocation Module comprising the RING-finger proteins PEX2, PEX10, and PEX12 conjugates a single ubiquitin to a cysteine residue of PEX5 (Carvalho et al. 2007, reviewed in Platta et al. 2016). The mono-ubiquitinated PEX5 and associated PEX7 are then extracted by the exportomer complex consisting of PEX1, PEX6, PEX26, and ZFAND6 (inferred from rat homologs in Miyata et al. 2012). PEX1 and PEX6 are members of the ATPases Associated with diverse cellular Activities (AAA) family, a group of proteins that use the energy of ATP hydrolysis to remodel molecular complexes. PEX1 and PEX6 form a hetero-hexameric ring, best described as a trimer of PEX1/PEX6 dimers (inferred from yeast in Platta et al. 2005, yeast homologs reviewed in Schwerter et al. 2017). Data on the yeast PEX1:PEX6 complex suggest that these ATPases use a substrate-threading mechanism to disrupt protein-protein interactions (Gardner et al. 2018). PEX7 is also then returned to the cytosol (Rodrigues et al. 2014). Once in the cytosol, ubiquitinated PEX5 is enzymatically deubiquitinated by USP9X and may also be non-enzymatically deubiquitinated by nucleophilic attack of the thioester bond between ubiquitin and the cysteine residue of PEX5 by small metabolites such as glutathione (Grou et al. 2012).
Defects in peroxisomal import cause human diseases: Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and rhizomelic chondrodysplasia punctata types 1 and 5 (Barøy et al. 2015, reviewed in Nagotu et al. 2012, Braverman et al. 2013, Wanders 2014, Fujiki 2016, Waterham et al. 2016).
Literature References
PubMed ID Title Journal Year
9090381 Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata

Gould, SJ, Steel, G, Braverman, N, Moser, A, Obie, C, Moser, H, Valle, D

Nat. Genet. 1997
27977397 ATP-driven processes of peroxisomal matrix protein import

Schwerter, DP, Platta, HW, Grimm, I, Erdmann, R

Biol. Chem. 2017
23798008 Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives

Braverman, NE, D'Agostino, MD, Maclean, GE

Dev Disabil Res Rev 2013
25854684 The peroxisomal protein import machinery displays a preference for monomeric substrates

Lismont, C, Domingues, P, Rodrigues, TA, Grou, CP, Freitas, MO, Azevedo, JE, Pinto, MP, Fransen, M, Francisco, T

Open Biol 2015
21976670 PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the N-terminal domain of PEX14

Sá-Miranda, C, Rodrigues, TA, Grou, CP, Freitas, MO, Carvalho, AF, Alencastre, IS, Azevedo, JE, Pinto, MP, Fransen, M, Francisco, T

J. Biol. Chem. 2011
22617146 Molecular basis of peroxisomal biogenesis disorders caused by defects in peroxisomal matrix protein import

Platta, HW, Kalel, VC, Nagotu, S, Erdmann, R

Biochim. Biophys. Acta 2012
26138649 Revisiting the intraperoxisomal pathway of mammalian PEX7

Rodrigues, TA, Grou, CP, Azevedo, JE

Sci Rep 2015
25177298 Peroxisome biogenesis in mammalian cells

Honsho, M, Mukai, S, Okumoto, K, Tamura, S, Fujiki, Y

Front Physiol 2014
26450166 Structural biology of the import pathways of peroxisomal matrix proteins

Emmanouilidis, L, Passon, DM, Wilmanns, M, Sattler, M, Gopalswamy, M

Biochim. Biophys. Acta 2016
17028012 Peroxisomal matrix protein receptor ubiquitination and recycling

Thoms, S, Erdmann, R

Biochim. Biophys. Acta 2006
16007078 Functional role of the AAA peroxins in dislocation of the cycling PTS1 receptor back to the cytosol

Rosenkranz, K, Platta, HW, Grunau, S, Erdmann, R, Girzalsky, W

Nat. Cell Biol. 2005
26220973 A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform

Westvik, J, Frengen, E, Barøy, T, Holmgren, A, Walter, J, Merckoll, E, Waterham, HR, Tvedt, B, Koster, J, Wanders, RJA, Stadskleiv, K, Hughes, T, Ferdinandusse, S, Wood, N, Misceo, D, Strømme, P, Woldseth, B, Ebberink, MS

Hum. Mol. Genet. 2015
11397814 Characterization of the mammalian peroxisomal import machinery: Pex2p, Pex5p, Pex12p, and Pex14p are subunits of the same protein assembly

Gouveia, AM, Sá-Miranda, C, Azevedo, JE, Reguenga, C, Oliveira, ME

J. Biol. Chem. 2001
20154681 The peroxisomal importomer constitutes a large and highly dynamic pore

Cizmowski, C, Schliebs, W, Beck, S, Meinecke, M, Wagner, R, Krüger, V, Erdmann, R

Nat. Cell Biol. 2010
26497277 Peroxisomal protein import pores

Meinecke, M, Wagner, R, Bartsch, P

Biochim. Biophys. Acta 2016
17726030 Ubiquitination of mammalian Pex5p, the peroxisomal import receptor

Sá-Miranda, C, Grou, CP, Carvalho, AF, Alencastre, IS, Azevedo, JE, Pinto, MP, Fransen, M

J. Biol. Chem. 2007
26408939 The first minutes in the life of a peroxisomal matrix protein

Rodrigues, TA, Grou, CP, Dias, AF, Azevedo, JE, Francisco, T

Biochim. Biophys. Acta 2016
28787099 Protein transport into peroxisomes: Knowns and unknowns

Barros-Barbosa, A, Rodrigues, TA, Dias, AF, Bicho, D, Azevedo, JE, Francisco, T

Bioessays 2017
24508507 Peroxisomes: a nexus for lipid metabolism and cellular signaling

Semenkovich, CF, Lodhi, IJ

Cell Metab. 2014
1680677 A novel, cleavable peroxisomal targeting signal at the amino-terminus of the rat 3-ketoacyl-CoA thiolase

Gould, SJ, Subramani, S, Rachubinski, RA, Swinkels, BW, Bodnar, AG

EMBO J. 1991
9668159 An isoform of pex5p, the human PTS1 receptor, is required for the import of PTS2 proteins into peroxisomes

Gould, SJ, Braverman, N, Valle, D, Dodt, G

Hum. Mol. Genet. 1998
27941306 Peroxisome biogenesis and human peroxisome-deficiency disorders

Fujiki, Y

Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 2016
26851075 Assembly, maintenance and dynamics of peroxisomes

Erdmann, R

Biochim. Biophys. Acta 2016
26367801 Regulation of peroxisomal matrix protein import by ubiquitination

Clausen, MP, Platta, HW, Brinkmeier, R, Reidick, C, Eggeling, C, Galiani, S

Biochim. Biophys. Acta 2016
10767286 The mammalian peroxin Pex5pL, the longer isoform of the mobile peroxisome targeting signal (PTS) type 1 transporter, translocates the Pex7p.PTS2 protein complex into peroxisomes via its initial docking site, Pex14p

Honsho, M, Kawai, A, Mukai, S, Ghaedi, K, Shimizu, N, Otera, H, Fujiki, Y, Harano, T, Tanaka, A

J. Biol. Chem. 2000
7719337 Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders

Gould, SJ, Watkins, P, Braverman, N, Moser, A, Valle, D, Moser, HW, Wong, C, Dodt, G

Nat. Genet. 1995
26611709 Human disorders of peroxisome metabolism and biogenesis

Waterham, HR, Wanders, RJA, Ferdinandusse, S

Biochim. Biophys. Acta 2016
22371489 Identification of ubiquitin-specific protease 9X (USP9X) as a deubiquitinase acting on ubiquitin-peroxin 5 (PEX5) thioester conjugate

Domingues, P, Sá-Miranda, C, Rodrigues, TA, Freitas, MO, Grou, CP, Carvalho, AF, Wood, SA, Azevedo, JE, Pinto, MP, Rodríguez-Borges, JE, Fransen, M, Francisco, T

J. Biol. Chem. 2012
21464226 Peroxisome assembly: matrix and membrane protein biogenesis

Subramani, S, Ma, C, Agrawal, G

J. Cell Biol. 2011
12885776 The energetics of Pex5p-mediated peroxisomal protein import

Sá-Miranda, C, Pinto, RA, Oliveira, ME, Gouveia, AM, Azevedo, JE

J. Biol. Chem. 2003
2654139 A conserved tripeptide sorts proteins to peroxisomes

Gould, SJ, Subramani, S, Keller, GA, Wilkinson, J, Hosken, N

J. Cell Biol. 1989
21980954 AWP1/ZFAND6 functions in Pex5 export by interacting with cys-monoubiquitinated Pex5 and Pex6 AAA ATPase

Miyata, N, Noguchi, M, Mukai, S, Okumoto, K, Fujiki, Y

Traffic 2012
29321502 The peroxisomal AAA-ATPase Pex1/Pex6 unfolds substrates by processive threading

Hurley, JH, Lander, GC, Stjepanovic, G, Castanzo, DT, Stefely, MS, Gardner, BM, Martin, A, Chowdhury, S

Nat Commun 2018
9653144 Identification of a human PTS1 receptor docking protein directly required for peroxisomal protein import

Subramani, S, Terlecky, SR, Fransen, M

Proc. Natl. Acad. Sci. U.S.A. 1998
8858165 Pex13p is an SH3 protein of the peroxisome membrane and a docking factor for the predominantly cytoplasmic PTs1 receptor

Bjorkman, J, Morrell, JC, Kalish, JE, Gould, SJ, Urquhart, AJ, Crane, DI

J. Cell Biol. 1996
3693402 Translocation of acyl-CoA oxidase into peroxisomes requires ATP hydrolysis but not a membrane potential

Lazarow, PB, Imanaka, T, Small, GM

J. Cell Biol. 1987
7579687 Import of stably folded proteins into peroxisomes

Walton, PA, Subramani, S, Hill, PE

Mol. Biol. Cell 1995
24865970 A PEX7-centered perspective on the peroxisomal targeting signal type 2-mediated protein import pathway

Rodrigues, TA, Grou, CP, Brites, P, Alencastre, IS, Azevedo, JE, Fransen, M, Francisco, T

Mol. Cell. Biol. 2014
22747494 Pex5p imports folded tetrameric catalase by interaction with Pex13p

Otera, H, Fujiki, Y

Traffic 2012
27284042 Peroxisome protein import: a complex journey

Lanyon-Hogg, T, Warriner, SL, Baker, A

Biochem. Soc. Trans. 2016
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