Peroxisomal protein import (Homo sapiens)
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Description
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.
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.
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peroxisomal
proteinsAnnotated Interactions
A minority of peroxisomal matrix proteins contain PTS2. While the PEX5S isoform binds proteins containing PTS1, the PEX5L isoform binds either proteins containing PTS1 or PEX7 bound to proteins containing PTS2 (Braverman et al. 1998). Some proteins appear to be imported as oligomers, however this is rather inefficient as PEX5 appears to have a preference for monomeric substrates (Otera and Fujiki 2012, Freitas et al. 2011, Freitas et al. 2015, also inferred from mouse homologs). Mutations in PEX5 cause defects in peroxisomal import and comprise complementation group 2 of peroxisomal biogenesis disorders (also called Zellweger spectrum disorders) (Dodt et al. 1995, Wiemer et al. 1995). A specific mutation affecting only the PEX5L isoform is the cause of rhizomelic chondrodysplasia punctate type 5 (Barøy et al. 2015).