Peroxisomal protein import (Homo sapiens)

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3, 4, 6, 9, 10, 12...855, 8, 22, 27, 36...8585, 988, 19, 36, 38, 56...53, 61, 68, 74, 87...42, 47, 55, 59, 62...18, 19, 21, 25, 56...15, 61, 68, 87, 9831, 35, 52, 82, 902, 5, 18, 21, 25...15, 61, 68, 87, 9885, 9831, 35, 52, 82, 901, 13, 14, 26, 27, 33...11, 17, 21, 31, 73...11, 17, 31, 73, 9018, 25, 27, 40, 5521, 53, 61, 68, 74...cytosolperoxisomal matrixUBB(153-228) RPS27A(1-76) PEX5 isoform S PEX5 isoform S PEX13 UBB(153-228) UBC(533-608) UBC(153-228) PEX5 isoform L Ub-C11-PEX5L UBB(153-228) PEX14 UBC(77-152) UBE2D3 IDE PEX5 isoform L UBC(609-684) UBC(229-304) IDH1 DECR2 PEX14 PEX12 UBC(153-228) ACOX1 PEX10 TYSND1 ACAA1(1-424) PEX10 PEX7 PEX10 PEX2 PEX7 UBC(77-152) ADPRPS27A(1-76) DDO UBC(153-228) Ub-C11-PEX5L AMACR UBB(1-76) ACOT4 ACOX3 Ub:PEX5LUBC(457-532) UBC(457-532) Ub:UBE2D1,2,3IDE PEX1 UBC(229-304) HACL1 UBC(381-456) PEX1 PEX5 isoform L PHYH(1-338) PEX14 UBC(1-76) RPS27A(1-76) UBC(229-304) UBC(533-608) AGPS(1-658) CROT CAT UBC(457-532) PEX2 UBB(77-152) EPHX2 RPS27A(1-76) ACOT8 UBB(1-76) SCP2 UBC(305-380) UBC(305-380) ECI2 UBC(533-608) BAAT UBC(229-304) CRAT UBB(77-152) UBB(153-228) UBC(1-76) PEX14 Ub-C85-UBE2D1 UBE2D2 PEX10 Ub-C85-UBE2D2 UBA52(1-76) UBC(1-76) UBC(609-684) Ub-C85-UBE2D2 ACOT4 PEX5L:PEX7:PEX13:PEX14:PEX2:PEX10:PEX12ACOT2(1-483) PEX2 UBE2D1 PEX12 UBC(457-532) UBC(153-228) ACAA1(1-424) PIPOX UbPAOX UBB(77-152) UBC(609-684) PEX2 UBB(1-76) GNPAT PEX14 UBC(1-76) UBB(77-152) RPS27A(1-76) PEX14 ACOX1 UBC(609-684) PEX13 PEX14 TYSND1 UBB(1-76) ACOT4 UBB(1-76) PEX5 isoform S HMGCL(1-325) CROT Ub:UBE2D1,2,3USP9XSCP2 UBB(77-152) MLYCD(40-493) PEX13:PEX14:PEX2:PEX10:PEX12NOS2 UBB(153-228) GNPAT UBB(153-228) Ub-C11-PEX5L EPHX2 TYSND1 NUDT19 UBA52(1-76) PEX5 isoform L ACOX2 DECR2 MPV17 PEX12 UBC(305-380) UBB(77-152) UBC(533-608) Ub:PEX5S,LUBC(533-608) UBC(229-304) EPHX2 UBA52(1-76) PEX1:PEX6:PEX26UBC(533-608) RPS27A(1-76) UBC(457-532) AGPS(1-658) ADPSLC27A2 UBC(1-76) ACAA1(1-424) Ub:PEX5SUBB(1-76) UBC(229-304) UBC(77-152) PEX12 UBC(153-228) PEX7:Cargo proteinsACOX3 UBC(457-532) PEX26 UBB(153-228) PXLP-AGXT PEX1 HACL1 PEX10 GSTK1 UBA52(1-76) UBE2D2 UBE2D1,2,3ECH1(1-328) GSTK1 UBC(77-152) UBC(533-608) DAO PIPOX Ub-C85-UBE2D1 NUDT19 UBC(77-152) UBC(153-228) DAO PEX5 isoform L UBC(1-76) UBC(457-532) PEX6 HAO1 PEX5 isoform S AMACR UBC(305-380) ECI2(39-394) PAOX UBC(457-532) UBC(77-152) UBC(153-228) UBC(381-456) UBC(609-684) PEX13 ACOX1 UBB(153-228) PEX14 DECR2 PEX2 DDO PEX10 UBC(1-76) USP9X UBC(609-684) PEX5 isoform SUBC(305-380) UBC(609-684) PECR ZFAND6UBC(305-380) UBA52(1-76) PEX7 PEX2 PIPOX USP9X PEX6 DHRS4 UBE2D1 UBC(305-380) HSD17B4(1-736) ACOT2(1-483) DAO UBB(1-76) UBC(153-228) UBC(229-304) UBC(381-456) HAO1 SLC27A2 UBC(229-304) ACOT2(1-483) DAO NUDT7 LONP2 UBC(229-304) PEX13 GSTK1 HAO2 ACOX2 PEX14 ACOX2 UBC(77-152) DHRS4 PEX7 UBC(305-380) UBB(77-152) ZFAND6USP9X:Ub:PEX5SRPS27A(1-76) IDH1 ECH1(1-328) UBB(1-76) UBC(229-304) HAO2 UBC(1-76) AGPS(1-658) HAO2 UBC(381-456) UBC(457-532) ACOX3 NUDT7 NUDT19 PHYH(1-338) PEX10 UBB(77-152) UBE2D1,2,3PEX5S,LUb-C11-PEX5L UBC(77-152) NOS2 CRAT UBC(77-152) UBC(229-304) UBB(153-228) UBC(609-684) Ub-C11-PEX5L RPS27A(1-76) UBC(457-532) ACOT8 UBC(533-608) UBC(381-456) MLYCD(40-493) PEX2 UBC(77-152) DHRS4 PEX12 UBC(77-152) UBC(457-532) UBB(153-228) UBA52(1-76) PEX26 PEX7 PEX5 isoform L Ub-C85-UBE2D1 UBC(381-456) UBA52(1-76) PEX5 isoform S RPS27A(1-76) UBC(305-380) ACAA1(1-424) H2OECH1(1-328) MPV17 Cargo proteinscontaining PTS2CAT USP9XPEX5 isoform LUBC(153-228) PEX14 AGPS(1-658) PEX5S,L:Cargo:PEX13:PEX14:PEX2:PEX10:PEX12DHRS4 PEX12 PEX7 UBC(305-380) PEX12 PEX12 UBC(1-76) HMGCL(1-325) UBB(77-152) NOS2 UBB(1-76) ZFAND6 UBC(305-380) CROT Ub-C11-PEX5S UBB(153-228) UBA52(1-76) IDE ECI2(39-394) ACOX3 HAO1 GNPAT RPS27A(1-76) HAO2 Ub-C11-PEX5S Ub-C11-PEX5L UBC(381-456) UBB(1-76) ATPBAAT UBC(1-76) UBC(153-228) DDO UBC(533-608) AMACR PEX13 SLC27A2 HSD17B4 PEX5S,L:PEX13:PEX14:PEX2:PEX10:PEX12UBB(153-228) PEX2:PEX10:PEX12:Ub:PEX5S,L:PEX13:PEX14Ub-C85-UBE2D3 PEX2:PEX10:PEX12:Ub:PEX5L:PEX7:PEX13:PEX14UBC(1-76) PEX13 PEX2:PEX10:PEX12:PEX5L:Ub:UBE2D1,2,3:PEX7:PEX13:PEX14Ub-C11-PEX5L PECR PEX12 Cargo proteinscontaining PTS1EPHX2 HSD17B4 UBB(77-152) PEX12 PEX2:PEX10:PEX12:Ub:PEX5L:PEX7:PEX13:PEX14:PEX1:PEX6:PEX26:ZFAND6UBC(153-228) LONP2 UBC(533-608) UBC(609-684) ATPPAOX UbPEX2 TYSND1 cleavesperoxisomalproteinsUBC(153-228) PEX5L:PEX7:Cargo:PEX13:PEX14:PEX2:PEX10:PEX12UBC(533-608) HAO1 UBC(609-684) UBC(1-76) ACOT4 UBC(609-684) ACOX2 IDE UBC(381-456) PEX26 SLC27A2 EHHADH UBB(153-228) PEX5 isoform L ACAA1(1-424) PEX7Ub-C85-UBE2D2 PEX12 ACOT8 AGXT UBC(457-532) UBC(229-304) UBC(533-608) PEX10 PHYH(1-338) UBA52(1-76) UBC(381-456) IDH1 UBB(1-76) UBC(381-456) LONP2 RPS27A(1-76) UBB(1-76) NUDT19 PEX5 isoform L UBC(381-456) UBC(305-380) MLYCD(40-493) UBB(77-152) UBC(381-456) PEX13 TYSND1 RPS27A(1-76) UBB(1-76) PEX14 UBC(305-380) PHYH(1-338) PAOX EHHADH PEX2:PEX10:PEX12:Ub:PEX5S,L:PEX1:PEX6:PEX26:ZFAND6UBC(153-228) Ub-C11-PEX5S Ub-C11-PEX5S ACOT8 GNPAT GSTK1 NUDT7 SCP2 UBC(533-608) UBB(77-152) PEX5 isoform L PEX1 UBA52(1-76) PECR BAAT UBC(77-152) PEX2 UBC(77-152) PEX13 Ub-C85-UBE2D3 UBB(77-152) DDO ZFAND6 UBA52(1-76) MLYCD(40-493) BAAT Cargo proteinscontaining PTS1AGPS(1-658) ECI2(39-394) HMGCL(1-325) UBC(457-532) UBC(305-380) UBC(1-76) EHHADH UBC(381-456) PEX6 PEX5L:PEX7:CargoproteinUBC(609-684) PEX2:PEX10:PEX12:PEX5S,L:Ub:UBE2D1,2,3:PEX13:PEX14UBC(229-304) UBA52(1-76) UBC(609-684) UBC(533-608) MPV17 PECR PHYH(1-338) Cargo proteinscontaining PTS2CAT PIPOX EHHADH UBC(305-380) NUDT7 UBC(229-304) PEX7 UBB(153-228) PEX10 CRAT Ub-C85-UBE2D2 PEX13 UBC(153-228) PEX10 ACOX1 PEX5S,L:CargoproteinUBC(229-304) UBB(77-152) PEX1:PEX6:PEX26RPS27A(1-76) PEX13 UBC(1-76) UBB(1-76) RPS27A(1-76) NOS2 ECH1(1-328) UBA52(1-76) UBB(1-76) H2OMPV17 CAT LONP2 UBB(77-152) UBC(77-152) SCP2 UBC(457-532) HACL1 PEX2 Ub-C85-UBE2D3 UBB(153-228) UBC(381-456) PEX2 UBC(457-532) RPS27A(1-76) PEX13 UBA52(1-76) Ub-C85-UBE2D1 CRAT UBE2D3 PEX6 HACL1 UBC(1-76) IDH1 UBC(381-456) ACOT2(1-483) UBC(153-228) PEX10 DECR2 AMACR AGXT AGXT USP9X:Ub:PEX5LPEX26 HMGCL(1-325) UBC(609-684) CROT UBC(533-608) Ub-C11-PEX5S UBA52(1-76) Ub-C85-UBE2D3 UBC(609-684) HSD17B4 UBC(77-152) 2531, 35, 7685234432, 543035, 76924926, 45, 586578435, 7626, 58298516, 58, 7886


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). View original pathway at:Reactome.


Pathway is converted from Reactome ID: 9033241
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

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  1. Gatto GJ, Geisbrecht BV, Gould SJ, Berg JM.; ''Peroxisomal targeting signal-1 recognition by the TPR domains of human PEX5.''; PubMed Europe PMC
  2. Nair DM, Purdue PE, Lazarow PB.; ''Pex7p translocates in and out of peroxisomes in Saccharomyces cerevisiae.''; PubMed Europe PMC
  3. Meinecke M, Bartsch P, Wagner R.; ''Peroxisomal protein import pores.''; PubMed Europe PMC
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  8. Francisco T, Rodrigues TA, Freitas MO, Grou CP, Carvalho AF, Sá-Miranda C, Pinto MP, Azevedo JE.; ''A cargo-centered perspective on the PEX5 receptor-mediated peroxisomal protein import pathway.''; PubMed Europe PMC
  9. Otera H, Harano T, Honsho M, Ghaedi K, Mukai S, Tanaka A, Kawai A, Shimizu N, Fujiki Y.; ''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.''; PubMed Europe PMC
  10. Emmanouilidis L, Gopalswamy M, Passon DM, Wilmanns M, Sattler M.; ''Structural biology of the import pathways of peroxisomal matrix proteins.''; PubMed Europe PMC
  11. Tamura S, Okumoto K, Toyama R, Shimozawa N, Tsukamoto T, Suzuki Y, Osumi T, Kondo N, Fujiki Y.; ''Human PEX1 cloned by functional complementation on a CHO cell mutant is respo