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 much less efficient than monomeric proteins (Freitas et al. 2011, inferred from mouse homologs in Freitas et al. 2015) so the role of transport of oligomers in vivo remains controversial (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 PEX13 and PEX14 at the peroxisomal membrane (Gould et al. 1996, Fransen et al. 1998). PEX14 exists in a complex with PEX2, PEX10, and PEX12 located at the peroxisome membrane (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 PEX7 may actually translocate into the peroxisome matrix. 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 ubiquitination and ATP (Imanaka et al. 1987, Thoms and Erdmann 2006, Carvalho et al. 2007). A ubiquitination module comprising PEX2, PEX10, and PEX12 conjugates ubiquitin to a cysteine residue of PEX5 (Carvalho et al. 2007, reviewed in Platta et al. 2016). The ubiquitinated PEX5 then interacts with the exportomer complex consisting of PEX1, PEX6, PEX26, and ZFAND6 (inferred from rat homologs in Miyata et al. 2012). PEX1 and PEX6 form a hexameric ring which hydrolyzes ATP to change conformation and extract PEX5 from the membrane (inferred from yeast in Platta et al. 2005, yeast homologs reviewed in Schwerter et al. 2017). PEX7 is also then returned to the cytosol (Rodrigues et al. 2014). Ubiquitinated PEX5 is actively deubiquitinated by USP9X and may also be passively deubiquitinated by uncatalyzed hydrolysis of the thioester bond between ubiquitin and the cysteine residue of PEX5 (Grou et al. 2012).
Defects in peroxisomal import cause human diseases: Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and rhizomelic chondrodysplasia punctata (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 PEX13 and PEX14 at the peroxisomal membrane (Gould et al. 1996, Fransen et al. 1998). PEX14 exists in a complex with PEX2, PEX10, and PEX12 located at the peroxisome membrane (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 PEX7 may actually translocate into the peroxisome matrix. 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 ubiquitination and ATP (Imanaka et al. 1987, Thoms and Erdmann 2006, Carvalho et al. 2007). A ubiquitination module comprising PEX2, PEX10, and PEX12 conjugates ubiquitin to a cysteine residue of PEX5 (Carvalho et al. 2007, reviewed in Platta et al. 2016). The ubiquitinated PEX5 then interacts with the exportomer complex consisting of PEX1, PEX6, PEX26, and ZFAND6 (inferred from rat homologs in Miyata et al. 2012). PEX1 and PEX6 form a hexameric ring which hydrolyzes ATP to change conformation and extract PEX5 from the membrane (inferred from yeast in Platta et al. 2005, yeast homologs reviewed in Schwerter et al. 2017). PEX7 is also then returned to the cytosol (Rodrigues et al. 2014). Ubiquitinated PEX5 is actively deubiquitinated by USP9X and may also be passively deubiquitinated by uncatalyzed hydrolysis of the thioester bond between ubiquitin and the cysteine residue of PEX5 (Grou et al. 2012).
Defects in peroxisomal import cause human diseases: Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and rhizomelic chondrodysplasia punctata (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 controversial as PEX5 appears to have a preference for monomeric substrates (Otera and Fujiki 2012, Freitas et al. 2011, 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).