Good things come to those who bait: the peroxisomal docking complex

Maximilian Rüttermann; Christos Gatsogiannis

doi:10.1515/hsz-2022-0161

Article Open Access

Good things come to those who bait: the peroxisomal docking complex

Maximilian Rüttermann and Christos Gatsogiannis

Published/Copyright: September 20, 2022

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information Explore this Subject

From the journal Biological Chemistry Volume 404 Issue 2-3

Abstract

Peroxisomal integrity and function are highly dependent on its membrane and soluble (matrix) components. Matrix enzymes are imported post-translationally in a folded or even oligomeric state, via a still mysterious protein translocation mechanism. They are guided to peroxisomes via the Peroxisomal Targeting Signal (PTS) sequences which are recognized by specific cytosolic receptors, Pex5, Pex7 and Pex9. Subsequently, cargo-loaded receptors bind to the docking complex in an initial step, followed by channel formation, cargo-release, receptor-recycling and -quality control. The docking complexes of different species share Pex14 as their core component but differ in composition and oligomeric state of Pex14. Here we review and highlight the latest insights on the structure and function of the peroxisomal docking complex. We summarize differences between yeast and mammals and then we integrate this knowledge into our current understanding of the import machinery.

Keywords: docking complex; peroxins; peroxisomal biogenesis; peroxisomal import; peroxisomal translocon

Introduction

Peroxisomes are highly versatile eukaryotic organelles that encapsulate particularly reactive metabolic pathways and contribute significantly to cellular redox balance and detoxification due to reduction of reactive oxygen species (Imanaka and Shimozawa 2019; Tolbert 1971; van den Bosch et al. 1992). They carry out a number of central and conserved processes such as β-oxidation of very long-chain fatty acids, metabolism of cholesterol and D-amino acids, oxidation of alcohols, synthesis of plasmalogens and bile acids, and polyamine catabolism (Dinis-Oliveira 2016; Imanaka and Shimozawa 2019) and have been recently discussed as important regulators of immune responses in human (Ferreira et al. 2019; Ganguli et al. 2019). Among the eukaryotes, some organisms have developed specialized peroxisomes. Trypanosomatid parasites harbor their glycolysis pathway in glycosomes (Haanstra et al. 2016), while plants require glyoxisomes for parts of their photorespiration (Tolbert 1971). Peroxisomes are highly adaptable to environmental conditions and more recently were shown to play vital roles in cellular stress response (Okumoto et al. 2020). There is also increasing evidence that impaired peroxisomal function is intertwined with age-related diseases (Cipolla and Lodhi 2017; Fransen et al. 2013) such as cancer (Dahabieh et al. 2018), diabetes and neurodegeneration (Imanaka and Shimozawa 2019). Defects of genes related to peroxisomal biogenesis and/or peroxisome-encapsulated processes lead to severe and life-threatening human diseases, often resulting in an early death (Honsho et al. 2020; Imanaka and Shimozawa 2019; Wanders and Waterham 2005; Waterham and Ebberink 2012).

Peroxisomes do not contain genetic information nor ribosomes (Lanyon-Hogg et al. 2010; McNew and Goodman 1994). However, it has been recently shown that ribosomes translating mRNA transcripts for proteins destined to peroxisomes are in close proximity to the peroxisomal membrane (Dahan et al. 2022). This supports the scenario that peroxisomal proteins might be synthetized and subsequently imported in a highly orchestrated and locally confined manner.

The import process of peroxisomal soluble enzymes in the lumen (matrix) of the organelle is cyclic and involves in general three major steps: cargo recognition, cargo translocation and receptor recycling. In this review, we will shortly summarize the current knowledge on the composition of the peroxisomal import machinery and then emphasize in particular on recent developments regarding the events taking place at the peroxisomal membrane during cargo-receptor-docking prior cargo translocation. In the past decades, yeasts have evolved as one of the most well established model organisms to study these processes, mainly because peroxisome proliferation can be easily induced by simply changing the carbon source (Evers 1991; Veenhuis et al. 1976). Here, we will therefore describe the respective pathways in yeast and highlight substantial important differences between the yeast and mammalian import machineries.

The peroxisomal import cycle in yeast and mammals

Cargo recognition

Soluble peroxisomal receptors, in baker’s yeast Saccharomyces cerevisiae (Sc), recognize their cargo proteins in the cytosol via the different Peroxisomal Targeting Signals (PTSs) (Gould et al. 1989; Klein et al. 2002; Kempiński et al. 2020; Swinkels et al. 1991). The majority of peroxisomal matrix enzymes carry a C-terminal PTS1 tripeptide and are recognized by the cytosolic receptor ScPex5 (Gould et al. 1989). Recently, two additional PTS1 cargo proteins, Pxp1 and Pxp2, have been identified. They contain the C-terminal signaling sequences PRL and VKL, respectively, expanding thus the range of putative peroxisomal enzymes and the PTS1 consensus sequence to [S/A/H/C/E/P/Q/V]-[K/R/H/Q]-[L/F] (Nötzel et al. 2016). The PTS1 peptide of the cargo binds thereby to a characteristic groove, formed by two clusters of tetratricopeptide repeats (TPRs) at the C-terminal half of ScPex5 (Gatto et al. 2000; McCollum et al. 1993). TPRs are well characterized scaffolds implicated in protein-protein interactions and assembly of large protein complexes (Zeytuni and Zarivach 2012) and also present in Tom20 and Tom70, of the mitochondrial import machinery (Baker et al. 2007). Recently, in oleic acid grown yeast cells, ScPex9, which is a ScPex5 paralogue, was also shown to join the PTS1 pathway and act as cytosolic receptor (Effelsberg et al. 2016; Yifrach et al. 2016). Cargo specificity was limited however to three peroxisomal proteins, namely ScMls1, ScMls2 and ScGto1 (Effelsberg et al. 2016; Rudowitz et al. 2020; Yifrach et al. 2016).

Several cargo enzymes are alternatively destined to the peroxisomal matrix via an N-terminal PTS2 nonapeptide ([R/K]-[L/V/I]-[X]5-[H/Q]-[L/A]) recognized by the receptor ScPex7 (Figure 1), but so far, this target signal has been identified in the sequence of only few enzymes (e.g. only two in yeast) (Kunze 2020; Swinkels et al. 1991). The ScPex7-cargo complex is further stabilized under distinct conditions either by the co-receptor ScPex21p or ScPex18p enabling recruitment to the peroxisomal membrane (Effelsberg et al. 2015; Purdue et al. 1998) (Figure 1).

Figure 1:

Peroxisomal receptors and membrane docking complexes in yeast and mammals. (A) Schematic structures of the main components of the yeast (left) and mammalian (right) import receptor- and membrane docking complexes involved in the PTS1 (green) and PTS2 import pathways (red background). Important structural regions are indicated. (B) The import receptors Pex5 and Pex7 are required for peroxisomal targeting of cargos tagged with either PTS1 or PTS2 signals. Mammalian cells harbor in contrast to yeast, at least two Pex5 splice variants HsPex5S (S for short) and HsPex5L (L for long). The longer HsPex5L variant joins as co-factor of HsPex7 in the PTS2 pathway (right), in homology to ScPex18p and ScPex21p in yeast (left). Binding of the cargo-receptor complexes is facilitated via the docking complex consisting of ScPex14, ScPex17 and ScPex13 in yeast (left) or Pex14 and Pex13 in mammals (right).

The PTS3 is a putative third import route, but less characterized and the associated “targeting signal” has not yet been precisely assigned. A potential PTS3 sequence has only been so far described in yeast as an internal signal patch of cargos lacking PTS1 or PTS2 (Kempiński et al. 2020). Interestingly, the respective cargos bind to the N-terminal domain of ScPex5 and not in the PTS1-recognising C-terminal TPR-region (Kempiński et al. 2020; Rymer et al. 2018; Yang et al. 2018) similar to the alcohol oxidase (Aox) from Hansenula polymorpha (Ozimek et al. 2006). Finally, cargos that generally lack a PTS sequence can be piggybacked and thus co-imported into peroxisomes upon binding to a typical cargo containing a PTS1 or PTS2 target sequence (Yang et al. 2018). Mdh2 binding to Mdh3 (Gabay-Maskit et al. 2020) and Pnc1 (Effelsberg et al. 2015; Kumar et al. 2016; Saryi et al. 2017) associating with the Gpd1 homodimer are characteristic examples for PTS1 and PTS2 piggybacking, respectively (Yang et al. 2018). Furthermore, Pex20 in Yarrowia lipolytica, a co-receptor of Pex7 joining the PTS2 pathway, has been shown to import Aox2 and Aox3 via direct binding (Chang and Rachubinski 2019).

Cargo translocation

The soluble cargo-loaded receptor is recruited to the peroxisomal membrane by the docking complex consisting mainly of ScPex14, ScPex17 and ScPex13 (Albertini et al. 1997; Chan et al. 2016; Erdmann and Blobel 1996; Huhse et al. 1998; Smith et al. 1997) (Figure 1B) and subsequently delivers its cargo into the peroxisomal matrix. In this process, it is still controversial whether the receptor ScPex5 is the main component of the translocation channel or rather passes the membrane through a channel that is formed by the docking complex. In the first scenario, the receptor is expected to undergo a metamorphosis (Lill et al. 2020; Meinecke et al. 2010, 2016) and similar to a pore forming toxin (Chen et al. 2021; Gatsogiannis et al. 2013), directly insert into the membrane, forming a highly dynamic pore facilitating cargo translocation (Erdmann and Schliebs 2005; Gouveia et al. 2000, 2003; Montilla-Martinez et al. 2015). In the alternative model, Pex5 is considered as a cargo-loaded shuttling receptor that is capable to enter the matrix through a central hydrophilic cavity formed exclusively by the docking complex (Dias et al. 2017).

Intriguingly, in contrast to import processes across the membranes of most other organelles, the peroxisomal translocon is highly adaptive and can tolerate cargos of different sizes (Meinecke et al. 2016; Walton et al. 1992; Yang et al. 2018). The peroxisomal matrix proteins can be thereby imported in their folded or even oligomeric state (McNew and Goodman 1994) similar to translocation events along the nuclear pore (Jovanovic-Talisman and Zilman 2017) or as described for the twin-arginine translocation (TAT) system in bacteria, chloroplasts and archaea (Frain et al. 2019). It should be noted, that the peroxisomal translocon is even capable to import up to 12 nm large artificial substrates (e.g. gold particles, oligosaccharides), as long as they are tagged with a PTS1-peptide (Walton et al. 1995; Yang et al. 2018).

Receptor recycling

Upon membrane insertion of the receptor ScPex5 and successful cargo-translocation, the receptor is ubiquitinated and further processed by the peroxisomal exportomer. Briefly, ubiquitination of ScPex5 involves the RING-complex, composed of ScPex2, ScPex10 and ScPex12 (Platta et al. 2004, 2007; Schliebs et al. 2010). Mono-ubiquitination induces recycling of the receptor and requires in addition the E2-enzyme ScPex4 and its activator ScPex22, whereas poly-ubiquitination involves the E2-enzyme ScUbc4 and primes the receptor for proteasomal degradation. A recent cryoEM structure of the RING-complex suggests the formation of a membrane-embedded channel by ScPex2, ScPEx10 and ScPex12 for the ubiquitination and retro-translocation of the receptor back to the cytosol (Feng et al. 2022). (poly)-Ub-Pex5 is then further exported from the membrane by the type II ATPAse complex ScPex1/ScPex6, that is anchored to the membrane by ScPex15 (Blok et al. 2015; Ciniawsky et al. 2015; Grimm et al. 2012; Platta et al. 2007; Tan et al. 2016). Notably, ATP is not required for the cargo import itself but rather for receptor recycling, supporting the notion of an export -driven import mechanism (Schliebs et al. 2010; Schwerter et al. 2017).

The mammalian docking process

Most differences in the composition of the respective assemblies in human and yeast are rather restricted to the receptor and docking complexes. In particular, in humans, there are two splice variants of the Homo sapiens (Hs) receptor HsPex5, HsPex5L for long and HsPex5S for short lacking 111 bp of exon 8 in the PEX5 gene (Braverman et al. 1998) (Figure 1A).

Both isoforms are capable to ferry cargos with the PTS1 signal and target them to the peroxisomal matrix (Braverman et al. 1998). The minority of the mammalian peroxisomal matrix proteins carrying the PTS2 signal, form first a complex with HsPex7 which is further targeted to the peroxisomes by HsPex5L (instead of ScPex18 and ScPex21 in yeast) (Braverman et al. 1998) (Figure 1B). The mammalian peroxisomal docking complex is also lacking the peripheral component ScPex17. The events of receptor/cargo docking, cargo translocation and receptor recycling are expected however to follow in general similar mechanistic principles in mammals and yeast. Important differences of the individual components are discussed in the subsequent sections.

Our focus will be on the peroxisomal docking complex, a crucial “checkpoint” for the receptor/cargo-complex at the peroxisomal membrane and in particular, on its key component Pex14 and its multifaceted role in receptor-cargo recognition.

Pex14 - the core component of the docking complex

ScPex14, a 38.4 kDa protein containing 384 residues (Albertini et al. 1997), is according to PaxDB (Wang et al. 2012) the most abundant peroxisomal membrane component (Barros-Barbosa et al. 2019). Its primary sequence consists of four distinct structural regions (Figure 2A). The N-terminal domain (N) is encoded by the residues 1 to 58 and connected via a 42 residue long flexible linker to a putative single transmembrane span (TM), an α-helix at residue 100 to 124 (Chan et al. 2016; Lill et al. 2020). Beyond the membrane, a short linker and two coiled-coil (CC) domains are predicted from residues 130 to 212 and 219 to 238, respectively (Chan et al. 2016; Lill et al. 2020). The C-terminal domain is predicted as mainly unstructured and highly flexible.

Figure 2:

Pex14 – the docking complex core component. (A) Schematic structure of ScPex14 (upper), HsPex14(lower) and mapped interaction sites with additional proteins. N-terminal domain (N, yellow), transmembrane domain (TM, blue), coiled-coil region (Cc, green) and unstructured regions (grey). (B) Secondary structure predicted via Alphafold2 of the human (AF-O75381-F1) and yeast (AF-P53112-F1) Pex14 isoform. Color legend: N-terminal domain-orange, transmembrane domain-blue, coiled-coil domain-green. (C) Structure of the mammalian Pex14(N) domain as cartoon (i. PDB 3FF5) and electrostatic surface (ii. PDB 3FF5), bound to Pex5-WxxxF-motif (iii. PDB 2W84), bound to Pex5-LxxxF-motif (iv. PDB 4BXU) and bound to Pex19 (v. PDB 2W85). The hydrophobic grooves 1 and 2, separated by F35 and F52 (grey), display an ideal binding site for the shown proteins (iii.-v.).

The HsPex14 primary structure encodes its N-terminal domain from residue 25 to 70, a TM α-helix from 110-138 (blue) and a single extended coiled-coil domain at residue 158–197 with flexible unstructured peptides (grey) in between (Oliveira et al. 2002) (Figure 2A). Whole protein structure predictions of the yeast (AF-P53112-F1) and human (AF-O75381-F1) Pex14 structure by Alphafold 2 (Jumper et al. 2021; Varadi et al. 2022) confirms the previous overall predicted domain organization (Figure 2B).

The N-terminal domain is considered an important interaction module of Pex14 and the peroxisomal docking complex. It contains binding sites for the PTS receptors (Williams et al. 2005), the chaperone of newly synthetized peroxisomal membrane proteins Pex19 (Neufeld et al. 2009; Sacksteder et al. 2000) and for β-tubulin (exclusively in HsPex14) (Figure 2A).

The structure of the highly conserved RnPex14(N) from rat has been solved using X-ray crystallography (Su et al. 2009) (Figure 2Ci. and ii.) and interactions of its human homologue HsPex14(N) with HsPex5 and HsPex19 have been well characterized by NMR spectroscopy (Neufeld et al. 2009; Neuhaus et al. 2014) (Figure 2Ciii. and v.). The available structures unravel a small globular bundle of three alpha-helices, namely α1, α2 and α3 (Figure 2C). Helices α1 and α2 show an antiparallel-arrangement and are connected by a short helical turn. Helix α3 is positioned diagonally, capping the helical pair of α1 and α2 (Figure 2C). On the opposite side, the α1-α2 pair includes the binding site with the receptor HsPex5, as well as for HsPex19 (Neufeld et al. 2009; Neuhaus et al. 2014) (Figure 2C).

The site exhibits two hydrophobic pockets, which are separated by two aromatic residues, Phe35 and Phe52 (Neufeld et al. 2009; Neuhaus et al. 2014) (Figure 2Cii). The conserved aromatic residues in the WxxxF/Y motif of HsPex5, Trp118 and Phe122, directly fit into the hydrophobic pockets of Pex14(N) (Neufeld et al. 2009; Su et al. 2009) (Figure 2Ciii). Furthermore, complementary charges between positively charged residues surrounding the hydrophobic pockets of HsPex14p(N) and negative patches of the HsPex5 ligand helix, including the WxxxF/Y motif, stabilize the interface. An additional HsPex14 binding motif (LxxxF), binding with lower affinity to the N-terminal than the previous identified WxxxF/Y has been found in Pex5 (Neuhaus et al. 2014) (Figurer 2Civ). Albeit this interaction competes with binding of HsPex19 (Neufeld et al. 2009) (Figurer 2Cv), β-tubulin (Reuter et al. 2021) and even the membrane surface (Gaussmann et al. 2021) (see below), Pex5 shows the highest affinity and therefore displaces the other bound proteins (Neufeld et al. 2009).

The minimal region of HsPex14 required to recover impaired protein import in mammalian cells includes residues 21–260 (Itoh and Fujiki 2006), which further confirms that the conserved N-terminal domain, the TM helix and the coiled-coil domain are essential for Pex14 function. Little is known however about the functional role of the unstructured C-terminal domain. Phosphorylation in specific C-terminal sites of Pex14 was shown to affect import efficiency of Catalase (Okumoto et al. 2020; Yamashita et al. 2020) and Cit2p (Schummer et al. 2020) in mammalian and yeast cells, respectively (Niederhoff et al. 2005). The ORF14 protein of the human pathogenic virus SARS-CoV-2 has been shown to target the C-terminal domain of Pex14, resulting in an import defect and mislocalisation of matrix proteins to the cytosol in SARS-CoV-2 infected cells (Knoblach et al. 2021).

Recent cryoEM and cross-linking MS data suggest that ScPex14 further oligomerizes to form characteristic homotrimers, resembling flexible rod-like particles (Lill et al. 2020) (Figure 3C). The elongated rods are formed by the two coiled-coil-domains, being perpendicular to the membrane (Lill et al. 2020). In addition to the strong interactions between the coiled-coil domains, further interactions are expected between the conserved AXXXA and GXXXG motifs of the TM domains, which are common helical interaction motifs in membrane proteins (Kleiger et al. 2002). Their ability to promote oligomerization has been indeed verified in the mammalian Pex14 isoform (Itoh and Fujiki 2006).

Figure 3:

Pex17 stabilizes the peroxisomal docking complex. Schematic (A) and alphafold 2 predicted secondary (B) structure (AF-P40155-F1-model_v2) of ScPex17 with the predicted transmembrane (TM, pink) and coiled-coil (Cc, yellow) domains, unstructured regions (grey). Mapped interaction sites of ScPex17 with additional components of the docking complex are displayed. (C) 2D-class averages of recombinant ScPex14 (C) and ScPex14/ScPex17 complex reconstituted into MSP1D1Δ4 nanodiscs (taken from (Lill et al. 2020)). (D) Schematic cartoon of the ScPex14/ScPex17 (green/yellow) complex arrangement in a 3:1 stoichiometry fitted into the cryoEM map of ScPex14/ScPex17 reconstituted in the MSP1D1Δ4 lipid nanodisc (Lill et al. 2020). Site and top view of simulated volume of the helical bundle assembly forming the ScPex14/ScPex17 rod. The volume was computed from polyalanine α-helices of coiled-coil domain 1 of Pex14 and Pex17, as identified in the original cryoEM map. (EMDB-12047) (Lill et al. 2020).

It is well established that the flexible unstructured C-terminus (and thus the rods formed by the coiled-coil domains) are directly facing the cytosol, but the data on the membrane topology of the N-terminal domain of Pex14(N) are rather contradictory. This is however a very important point, since this multi-purpose protein-interaction platform is crucial for peroxisomal function (Gaussmann et al. 2021; Neufeld et al. 2009; Reuter et al. 2021; Su et al. 2009).

We would like to emphasize here, that the C-terminus of ScPex14 includes an exclusive second site of interaction with the PTS receptors (Niederhoff et al. 2005). Most importantly, deletion of the N-terminal PTS binding site of ScPex14 reduces PTS1 matrix protein import, whereas the truncation of the C-terminal binding site completely blocks it (Niederhoff et al. 2005). It should also be noted, that the yeast PTS2-receptor ScPex7 binds exclusively to the C-terminus of ScPex14 (Niederhoff et al. 2005). This suggests the C-terminal sites (facing the cytosol) as the primary docking sites for the PTS receptors in yeast and a different role for the binding-site in the N-terminal domain.

This is in contrast to the literature data for HsPex14, which is suggested to exclusively bind PTS receptors via its N-terminal domain (Gouveia et al. 2000; Itoh and Fujiki 2006; Schliebs et al. 1999). This might also support the notion that several aspects of the mechanism of receptor recognition and subsequent cargo translocation might differ in detail in human and yeast.

The yeast Pex14/Pex17 complex

ScPex17 is considered as an additional core component of the docking complex in yeast, but so far a homologue has not been yet detected in higher eukaryotes (Smith et al. 1997). ScPex17 is a helical peroxisomal membrane protein with a putative TMD at residue 35 to 55 and two coiled-coil domains at residue 71 to 89 and 125 to 140 exposing into the cytosol (Chan et al. 2016; Lill et al. 2020) (Figure 3A). The TMD and each coiled-coil domain have been predicted by alphafold2 (AF-P40155-F1-model_v2) as α-helices separated by flexible linker of different length which is in line with previous predicted domain organization showing a linear organization (Figure 3B). ScPex17 was shown to highly increase the efficiency of receptor docking at the peroxisomal membrane, both for the PTS1 and PTS2 import pathways (Chan et al. 2016; Girzalsky et al. 2006). Recent cryoEM studies on ScPex14/Pex17 indicate that ScPex17-binding further stabilizes the rod-shaped homotrimers of ScPex14 (Lill et al. 2020) (Figure 3C). Along this line, a recent cryoEM structure of the ScPex14/ScPex17 complex reconstituted in lipid nanodiscs, in combination with cross-linking-, native-MS and size-exclusion chromatography combined with multi angle light scattering (SEC-MALS) data, revealed a 3:1 stoichiometric assembly and a parallel arrangement of ScPex14 and ScPex17p along their complete sequence (Lill et al. 2020). A single copy of ScPex17 is thereby running parallel to the elongated rod, that is mainly formed by three copies of the predicted coiled-coil domains of ScPex14 (Lill et al. 2020) (Figure 3D). Thus, the coiled-coil domain of ScPex17 is closely associated with this characteristic homotrimeric parallel helix arrangement, resulting in an intriguing helix bundle with pseudo four-fold symmetry (Lill et al. 2020) (Figure 3D). Lill et al. (2020) have identified a total of 13 residue pairs over both coiled-coil domains using cross-linking MS in combination with quantitative MS involved in these interactions. The bundle does not have a typical rigid coiled-coil structure but contains multiple kinks and weak connections that could allow for a higher degree of flexibility and the expected large conformational changes in binding of cargo-loaded PTS receptors to ScPex14. The TM domain (a total of 4 TM helices) of ScPex14/ScPex17 is not resolved in the cryoEM density.

The C-terminal density beyond the coiled-coil domains also did not reach interpretable resolution, which further confirms a higher degree of flexibility, matching the alphafold prediction (Figure 2B). Interestingly, the flexible 120 aa unstructured C-termini of ScPex14, including the primary PTS receptor binding sites in yeast, do not exhibit homo-multimeric linkages (Chan et al. 2016; Lill et al. 2020). It is tempting to speculate that ScPex14/ScPex17 functions similar to a fishing rod. The coiled-coil region may be thought of as the “blank”, the C-terminal elongated peptides as the “line”, and the PTS receptor binding site as the “bait and hook” (Figure 3D). Together, these components can “fish” for cargo-loaded receptors and bring them in close vicinity to the peroxisomal membrane for further translocation events (Lill et al. 2020).

Several 2D cryoEM averages of ScPex14/ScPex17 in Lill et al. (2020) show the N-terminal globular domain of Pex14 as a flexible density below the nanodisc. This is consistent with the alphafold prediction showing the N-terminal globular domain connected to the TM domain via a long flexible linker (Figure 2B). Immunogold labeling of the N-terminus of ScPex14 further confirms that both termini are separated by the lipid bilayer in the ScPex14/ScPex17 complex (Lill et al. 2020). This agrees with the N_in-C_out topology proposed for the HsPex14 complex based on protease protection assays of HsPex14 complexes reconstituted in proteoliposomes (Barros-Barbosa et al. 2019). However, the topology of Pex14 is expected to be far more dynamic which will be addressed later within this review.

The ScPex14/ScPex17 complex is to our knowledge the minimal peroxisomal docking complex in yeast (Meinecke et al. 2010). However, high molecular mass complexes incl. Pex14, Pex17, Pex13 and the components of the export machinery, Pex10 and Pex12, were isolated from peroxisomal membranes upon affinity purification of Pex5, indicating that higher order molecular weight complexes must be assembled for efficient import (Chan et al. 2016; Meinecke et al. 2010). The dynein light chain protein Dyn2 is an additional component of the docking complex exclusively in yeast (Chang et al. 2013, 2016) and was shown to associate with the coiled-coil domains of Pex14 and Pex17 in a Pex17-dependent manner. In addition, it has also been shown to interact with the SH3-binding motif of ScPex13 (Chan et al. 2016). Dyn2 is proposed to act as a molecular glue, supporting formation and/or stabilization of large molecular assemblies of the importomer, similar to its role in stabilizing the Nup82-Nsp1-Nup159 complexes of cytoplasmic pore filaments of the nuclear pore complex (Chang et al. 2013; Stelter et al. 2007). Indeed, absence of Dyn2 results in the decrease of the higher order complexes of the docking/translocation machinery. It is however not yet clear whether physical binding between HsPex14 and HsDyn2 also occurs in human cells.

Pex13 - the other key component of the docking complex

Yeast and mammals share Pex13 as an additional membrane component of the peroxisomal docking complex crucially involved in the PTS1 and PTS2 import pathways (Elgersma et al. 1996; Erdmann and Blobel 1996; Gould et al. 1996). The ∼42–44 kDa Pex13 is composed of two structural conserved regions: several putative transmembrane domains flanking a Pex14 binding site (Schell-Steven et al. 2005) and a highly important SH3 domain (Gould et al. 1996) (Figure 4A). The structure of the globular ScPex13 Src homology 3 (SH3) domain has been solved and analyzed using X-ray crystallography and NMR spectroscopy (Douangamath et al. 2002; Pires et al. 2003; Williams and Distel 2006). The overall β-barrel fold exposes a patch of hydrophobic residues forming a pocket suitable for the PXXP motif of Pex14(N) from yeast (Pires et al. 2003) and human (Douangamath et al. 2002) (Figure 4B). Furthermore, the opposite site exposes an additional hydrophobic binding site with specificity for the N-terminal WXXXF/Y motif of Pex5 (Bottger et al. 2000; Douangamath et al. 2002; Pires et al. 2003) (Figure 4B). Therefore, the SH3 domain of Pex13 is considered a critically switch in the import process and its absence or defect results in growth defect on methanol in yeast (Gould et al. 1996) or peroxisome deficiency in human (Krause et al. 2013).

Figure 4:

Pex13 interacting with Pex5 and Pex14. (A) Schematic structure of the yeast and human Pex13 protein. Unstructured regions are displayed grey. The putative transmembrane region (blue striped) was predicted with TMHMM 2.0 (Krogh et al. 2001; Sonnhammer et al. 1998). The prediction did not allow to interpret whether the four identified transmembrane domains are full spanning. Therefore, we avoid any assumptions about the actual transmembrane topology. The Src homology 3 (SH3) domain is displayed purple. (B) Structure of the Pex13 SH3 domain (PDB: 1N5Z). The color of the surface represents the level of hydrophobicity (yellow: Hydrophobic, blue: hydrophilic). The SH3 domain exposes two opposite binding sites for the Pex5 WXXX(F/Y) and Pex14 PXXP motifs. The actual binding of the Pex14 PXXP motif to the Pex13 SH3 domain is shown.

Indeed, Pex5 was shown to bind to either Pex14 or Pex13 in a cargo-dependent manner in mammals, with higher affinity for Pex14 when cargo is bound and for Pex13 when cargo is not bound (Otera et al. 2002; Urquhart et al. 2000). Furthermore, the major fraction of ScPex13 does not co-purify together with ScPex14/17 (Agne et al. 2003), cargo-free Pex5 induces the disassembly of Pex14-homo-oligomers (Itoh and Fujiki 2006) and Pex14 and Pex5 were shown to compete for binding to the SH3 domain of Pex13 (Urquhart et al. 2000). There is thus a dynamic interplay between Pex5, Pex14 and Pex13, involving numerous interactions, which apparently however largely depend on the respective stage of the cargo-docking and -unloading events. Based on the assumption, that the described interactions properties reflect the situation in vivo, it has been postulated that cargo-loaded Pex5 initially binds with high affinity to Pex14. Binding to Pex13, might occur later, during or after cargo release, mediating thus the shuttling of the receptor back to the cytosol (Rayapuram and Subramani 2006; Urquhart et al. 2000).

The fact that Pex5 contains a single LVAEF site and multiple sequential and linear WXXX(F/Y) binding motifs to Pex14, has led to the suggestion that Pex14(N) might first “dock” to LVAEF and then step-by-step, “slide” along the respective sequence of cargo-loaded Pex5 (Neuhaus et al. 2014; Schliebs et al. 1999). These events might allow transfer of the Pex14(N) towards the SH3 of Pex13 and of the cargo towards the peroxisomal matrix. This might induce pore assembly and finally cargo release once the two WXXX(F/Y) downstream motifs six and seven are reached (Freitas et al. 2011; Neuhaus et al. 2014). Pex13 binds to WXXX(F/Y) motifs 2–4 of Pex5, and according to the “sliding”-model, might thus be crucial in pore-assembly or disassembly and cargo release (Neuhaus et al. 2014). This might also partially explain the controversy on the membrane topology of the Pex13(SH3) (Barros-Barbosa et al. 2019), but the required biochemical and structural data on these events have remained scarce.

Conclusions and future perspectives

Pex14 is a central membrane protein in peroxisome biology. Binding of the cargo-loaded receptors to Pex14 triggers a plethora of interactions and the formation of higher-order complexes. These are required for the formation of the translocation channel and subsequent receptor recycling.

Furthermore, HsPex14 anchors peroxisomes to microtubules with nanomolar affinity (Bharti et al. 2011; Reuter et al. 2021) playing an important regulatory role in peroxisome mobility (Neuhaus et al. 2016). ScPex14 binds on the other hand strongly to Dyn2 (Chang et al. 2013, 2016), but this has been correlated rather with a direct role in the importomer assembly and not in peroxisome motility (Chang et al. 2013). More recently, a competitive correlation between matrix protein import and anchoring to microtubules has been suggested, as the PTS1 receptor HsPex5 prevents HsPex14 binding to β-tubulin (Reuter et al. 2021).

Recombinantly expressed ScPex14/ScPex17 was recently reconstituted in liposomes and subsequently visualized by cryo electron tomography: Rod-shaped filamentous ScPex14/17 particles were shown to isotropically decorate the surface of liposomes without forming higher-order assemblies or affecting membrane curvature (Lill et al. 2020). For such a versatile binding platform for cargo-shuttling receptors and microtubule tethering, a membrane-bound, rod-shaped filamentous structure would certainly present advantages. It is tempting to speculate that peroxisomes might be decorated in a similar "sea urchin"-like manner by large numbers of flexible ScPex14/ScPex17 filament particles, given that Pex14 is the most abundant peroxisomal membrane protein and native ScPex14/17 complexes solubilized from whole cell membranes, do exhibit this characteristic elongated architecture (Lill et al. 2020). However, the docking complex has not yet been visualized directly at the peroxisomal membrane. Despite recent developments in cryo-EM, the elongated and highly flexible structure of Pex14 poses a major challenge in this direction. Moreover, the addition of important components of the docking complex, such as Pex13 or Dyn2 in yeast, could lead to transient complexes with completely different architectures. Nevertheless, the filamentous structure of the yeast Pex14 complex, with its primary PTS receptor binding site at the flexible C-terminal tail facing the cytosol (Niederhoff et al. 2005) and the second N-terminal receptor binding site on the opposite site of the membrane, renders a two-step model of receptor docking attractive:

in a first step, the C-terminus of ScPex14 is the actual docking site for the receptor ScPex5 (Niederhoff et al. 2005)
This event triggers formation of a pore by ScPex5p (Erdmann and Schliebs 2005; Meinecke et al. 2010). Alternatively, the pore is formed by the components of the docking complex (Dias et al. 2017).
interaction between cargo-loaded ScPex5 and the matrix-facing N-terminal domain of ScPex14 would thus occur in a second step either after membrane insertion of ScPex5 (Lill et al. 2020; Niederhoff et al. 2005) or its passage through a central cavity formed by the docking complex (Dias et al. 2017). This interaction may be important for the formation of the translocation channel, its stabilization (Lill et al. 2020; Niederhoff et al. 2005) and/or cargo release.

In this sense, several studies are in agreement on the N_in-C_out topology of Pex14 in different organisms (Barros-Barbosa et al. 2019; Lill et al. 2020; Oliveira et al. 2002), whereas a plethora of studies rather suggests the involvement of Pex5 into pore formation events. Pex14 has been shown to form a stable complex with membrane-bound Pex5, which in turn exhibits properties of an integral membrane protein (Gouveia et al. 2000; Kerssen et al. 2006; Urquhart et al. 2000). Binding of HsPex5 shows also significant affinity to the membrane and docking of the HsPex5 to HsPex14 at the membrane does not alter the affinity between both proteins (Gaussmann et al. 2021).

However, with respect to mammalian Pex14, there are the following important arguments against such a two-step mechanism: If the N-terminal domain is the only structural region of mammalian Pex14 containing a receptor binding site, a N_in-C_out topology would be inconsistent with its main function of “fishing” cytosolic receptors ferrying cargos (Oliveira et al. 2002; Shimizu et al. 1999). In addition, Shimizu et al. (1999) suggested a N_out-C_out topology based on epitope labeling of the termini (Shimizu et al. 1999). Most importantly, a N_in-C_out topology is also inconsistent with the high-affinity binding of HsPex14 to β-tubulin required for peroxisome mobility, because the β-tubulin-binding site of HsPex14 is localized in the N-terminal domain (Bharti et al. 2011; Reuter et al. 2021). A simple explanation might be that several aspects of the underlying mechanisms might differ in detail between yeast and mammalian Pex14. For example, HsPex14 does not include the second predicted coiled-coil domain and is not further stabilized by Pex17. However, it is rather interesting to conclude, given the overall structural conservation of Pex14, that such conflicting results might rather represent mechanistic snapshots of a very dynamic complex.

This view would agree with the recent exciting finding that mitotic phosphorylation of HsPex14 induces drastic conformational changes that result in the protection of Pex14(N) from proteolytic digestion, indicating thus in this case a clear topological change of the N-terminal domain of HsPex14 (Yamashita et al. 2020). Furthermore, interaction with other membrane peroxins of the importomer machinery and assembly of higher order complexes, might also affect the topology of the N-terminal domain. For example, the Pex14(N) might shift from the cytosol into the peroxisomal matrix upon Pex5 docking, following the expected drastic conformational changes of cargo-loaded Pex5 and its insertion into the membrane. Such conformational changes would be also in accordance with the “sliding” model (Neuhaus et al. 2014), with the N-terminal domain of Pex14 sliding and “scanning” the sequential WXXX(F/Y) binding-motifs of Pex5, with each dislocation triggering a step of the process (docking → membrane insertion → pore assembly → cargo release → pore disassembly). The precise role of the other core component of the docking complex Pex13, in this process, remains unclear.

One of most exciting challenges towards understanding this complex series of events triggered upon receptor-cargo docking at the peroxisomal membrane, remains thus the detailed structural investigation of the importomer and exportomer machineries and their individual components.

Corresponding author: Christos Gatsogiannis, Institute for Medical Physics and Biophysics and Center for Soft Nanoscience, Westfälische Wilhelms Universität Münster, D-48149 Münster, Germany, E-mail: christos.gatsogiannis@uni-muenster.de

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: GA 2519/1-2

Acknowledgements

We thank Wolfgang Girzalsky and Wolfgang Schliebs for critical reading of the manuscript and their useful advice.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This study has been supported by the Deutsche Forschungsgemeinschaft to Christos Gatsogiannis (GA 2519/1-2) via the joint research group PerTRANS (DFG FOR 1905).
Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
Note added in proof: During the review of this article, we became aware of a recent study by Skowyra and Rapoport (2022) supporting the latter model, in which Pex5 rather crosses the membrane and moves into the peroxisomal lumen to release its cargo. The mechanistic details and precise role of the docking complex and Pex14 in this process remain enigmatic.

References

Agne, B., Meindl, N.M., Niederhoff, K., Einwächter, H., Rehling, P., Sickmann, A., Meyer, H.E., Girzalsky, W., and Kunau, W.-H. (2003). Pex8p: an intraperoxisomal organizer of the peroxisomal import machinery. Mol. Cell 11: 635–646, https://doi.org/10.1016/s1097-2765(03)00062-5.Search in Google Scholar PubMed

Albertini, M., Rehling, P., Erdmann, R., Girzalsky, W., Kiel, J.A., Veenhuis, M., and Kunau, W.-H. (1997). Pex14p, a peroxisomal membrane protein binding both receptors of the two PTS-dependent import pathways. Cell 89: 83–92, https://doi.org/10.1016/s0092-8674(00)80185-3.Search in Google Scholar PubMed

Baker, M.J., Frazier, A.E., Gulbis, J.M., and Ryan, M.T. (2007). Mitochondrial protein-import machinery: correlating structure with function. Trends Cell Biol. 17: 456–464, https://doi.org/10.1016/j.tcb.2007.07.010.Search in Google Scholar PubMed

Barros-Barbosa, A., Ferreira, M.J., Rodrigues, T.A., Pedrosa, A.G., Grou, C.P., Pinto, M.P., Fransen, M., Francisco, T., and Azevedo, J.E. (2019). Membrane topologies of PEX13 and PEX14 provide new insights on the mechanism of protein import into peroxisomes. FEBS J. 286: 205–222, https://doi.org/10.1111/febs.14697.Search in Google Scholar PubMed

Bharti, P., Schliebs, W., Schievelbusch, T., Neuhaus, A., David, C., Kock, K., Herrmann, C., Meyer, H.E., Wiese, S., Warscheid, B., et al.. (2011). PEX14 is required for microtubule-based peroxisome motility in human cells. J. Cell Sci. 124: 1759–1768, https://doi.org/10.1242/jcs.079368.Search in Google Scholar PubMed

Blok, N.B., Tan, D., Wang, R.Y.-R., Penczek, P.A., Baker, D., DiMaio, F., Rapoport, T.A., and Walz, T. (2015). Unique double-ring structure of the peroxisomal Pex1/Pex6 ATPase complex revealed by cryo-electron microscopy. Proc. Natl. Acad. Sci. U.S.A. 112: E4017–E4025, https://doi.org/10.1073/pnas.1500257112.Search in Google Scholar PubMed PubMed Central

Bottger, G., Barnett, P., Klein, A.T., Kragt, A., Tabak, H.F., and Distel, B. (2000). Saccharomyces cerevisiae PTS1 receptor Pex5p interacts with the SH3 domain of the peroxisomal membrane protein Pex13p in an unconventional, non-PXXP-related manner. Mol. Biol. Cell 11: 3963–3976, https://doi.org/10.1091/mbc.11.11.3963.Search in Google Scholar PubMed PubMed Central

Braverman, N., Dodt, G., Gould, S.J., and Valle, D. (1998). An isoform of pex5p, the human PTS1 receptor, is required for the import of PTS2 proteins into peroxisomes. Hum. Mol. Genet. 7: 1195–1205, https://doi.org/10.1093/hmg/7.8.1195.Search in Google Scholar PubMed

Chan, A., Schummer, A., Fischer, S., Schröter, T., Cruz-Zaragoza, L.D., Bender, J., Drepper, F., Oeljeklaus, S., Kunau, W.-H., Girzalsky, W., et al.. (2016). Pex17p-dependent assembly of Pex14p/Dyn2p-subcomplexes of the peroxisomal protein import machinery. Eur. J. Cell Biol. 95: 585–597, https://doi.org/10.1016/j.ejcb.2016.10.004.Search in Google Scholar PubMed

Chang, J. and Rachubinski, R.A. (2019). Pex20p functions as the receptor for non-PTS1/non-PTS2 acyl-CoA oxidase import into peroxisomes of the yeast Yarrowia lipolytica. Traffic 20: 504–515, https://doi.org/10.1111/tra.12652.Search in Google Scholar PubMed

Chang, J., Tower, R.J., Lancaster, D.L., and Rachubinski, R.A. (2013). Dynein light chain interaction with the peroxisomal import docking complex modulates peroxisome biogenesis in yeast. J. Cell Sci. 126: 4698–4706, https://doi.org/10.1242/jcs.129056.Search in Google Scholar PubMed PubMed Central

Chen, M., Blum, D., Engelhard, L., Raunser, S., Wagner, R., and Gatsogiannis, C. (2021). Molecular architecture of black widow spider neurotoxins. Nat. Commun. 12: 6956, https://doi.org/10.1038/s41467-021-26562-8.Search in Google Scholar PubMed PubMed Central

Ciniawsky, S., Grimm, I., Saffian, D., Girzalsky, W., Erdmann, R., and Wendler, P. (2015). Molecular snapshots of the Pex1/6 AAA+ complex in action. Nat. Commun. 6: 7331, https://doi.org/10.1038/ncomms8331.Search in Google Scholar PubMed PubMed Central

Cipolla, C.M. and Lodhi, I.J. (2017). Peroxisomal dysfunction in age-related diseases. Trends Endocrinol. Metabol. 28: 297–308, https://doi.org/10.1016/j.tem.2016.12.003.Search in Google Scholar PubMed PubMed Central

Dahabieh, M.S., Di Pietro, E., Jangal, M., Goncalves, C., Witcher, M., Braverman, N.E., and Del Rincón, S.V. (2018). Peroxisomes and cancer: the role of a metabolic specialist in a disease of aberrant metabolism. Biochim. Biophys. Acta, Rev. Cancer 1870: 103–121, https://doi.org/10.1016/j.bbcan.2018.07.004.Search in Google Scholar PubMed

Dahan, N., Bykov, Y.S., Boydston, E.A., Fadel, A., Gazi, Z., Hochberg-Laufer, H., Martenson, J., Denic, V., Shav-Tal, Y., Weissman, J.S., et al.. (2022). Peroxisome function relies on organelle-associated mRNA translation. Sci. Adv. 8: eabk2141, https://doi.org/10.1126/sciadv.abk2141.Search in Google Scholar PubMed PubMed Central

Dias, A.F., Rodrigues, T.A., Pedrosa, A.G., Barros-Barbosa, A., Francisco, T., and Azevedo, J.E. (2017). The peroxisomal matrix protein translocon is a large cavity-forming protein assembly into which PEX5 protein enters to release its cargo. J. Biol. Chem. 292: 15287–15300, https://doi.org/10.1074/jbc.m117.805044.Search in Google Scholar

Dinis-Oliveira, R.J. (2016). Oxidative and non-oxidative metabolomics of ethanol. Curr. Drug Metabol. 17: 327–335, https://doi.org/10.2174/1389200217666160125113806.Search in Google Scholar PubMed

Douangamath, A., Filipp, F.V., Klein, A.T., Barnett, P., Zou, P., Voorn-Brouwer, T., Vega, M., Mayans, O.M., Sattler, M., Distel, B., et al.. (2002). Topography for independent binding of α-helical and PPII-helical ligands to a peroxisomal SH3 domain. Mol. Cell 10: 1007–1017, https://doi.org/10.1016/s1097-2765(02)00749-9.Search in Google Scholar PubMed PubMed Central

Effelsberg, D., Cruz-Zaragoza, L.D., Schliebs, W., and Erdmann, R. (2016). Pex9p is a new yeast peroxisomal import receptor for PTS1-containing proteins. J. Cell Sci. 129: 4057–4066.10.1242/jcs.195271Search in Google Scholar

Effelsberg, D., Cruz-Zaragoza, L.D., Tonillo, J., Schliebs, W., and Erdmann, R. (2015). Role of Pex21p for piggyback import of Gpd1p and Pnc1p into peroxisomes of Saccharomyces cerevisiae. J. Biol. Chem. 290: 25333–25342, https://doi.org/10.1074/jbc.m115.653451.Search in Google Scholar

Elgersma, Y., Kwast, L., Klein, A., Voorn-Brouwer, T., van den Berg, M., Metzig, B., America, T., Tabak, H.F., and Distel, B. (1996). The SH3 domain of the Saccharomyces cerevisiae peroxisomal membrane protein Pex13p functions as a docking site for Pex5p, a mobile receptor for the import PTS1-containing proteins. J. Cell Biol. 135: 97–109, https://doi.org/10.1083/jcb.135.1.97.Search in Google Scholar PubMed PubMed Central

Erdmann, R. and Blobel, G. (1996). Identification of Pex13p a peroxisomal membrane receptor for the PTS1 recognition factor. J. Cell Biol. 135: 111–121, https://doi.org/10.1083/jcb.135.1.111.Search in Google Scholar PubMed PubMed Central

Erdmann, R. and Schliebs, W. (2005). Peroxisomal matrix protein import: the transient pore model. Nat. Rev. Mol. Cell Biol. 6: 738–742, https://doi.org/10.1038/nrm1710.Search in Google Scholar PubMed

Evers, M. (1991). Physiological studies on the utilization of oleic acid by Saccharomyces cerevisiae in relation to microbody development. FEMS Microbiol. Lett. 90: 73–78, https://doi.org/10.1111/j.1574-6968.1991.tb05128.x.Search in Google Scholar

Feng, P., Wu, X., Erramilli, S.K., Paulo, J.A., Knejski, P., Gygi, S.P., Kossiakoff, A.A., and Rapoport, T.A. (2022). A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel. Nature. 607: 374–380.10.1038/s41586-022-04903-xSearch in Google Scholar PubMed PubMed Central

Ferreira, A.R., Marques, M., and Ribeiro, D. (2019). Peroxisomes and innate immunity: antiviral response and beyond. Int. J. Mol. Sci. 20, https://doi.org/10.3390/ijms20153795.Search in Google Scholar PubMed PubMed Central

Frain, K.M., Robinson, C., and van Dijl, J.M. (2019). Transport of folded proteins by the Tat system. Protein J. 38: 377–388, https://doi.org/10.1007/s10930-019-09859-y.Search in Google Scholar PubMed PubMed Central

Fransen, M., Nordgren, M., Wang, B., Apanasets, O., and van Veldhoven, P.P. (2013). Aging, age-related diseases and peroxisomes. Sub Cell. Biochem. 69: 45–65.10.1007/978-94-007-6889-5_3Search in Google Scholar PubMed

Freitas, M.O., Francisco, T., Rodrigues, T.A., Alencastre, I.S., Pinto, M.P., Grou, C.P., Carvalho, A.F., Fransen, M., Sá-Miranda, C., and Azevedo, J.E. (2011). PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the N-terminal domain of PEX14. J. Biol. Chem. 286: 40509–40519, https://doi.org/10.1074/jbc.m111.287201.Search in Google Scholar PubMed PubMed Central

Gabay-Maskit, S., Cruz-Zaragoza, L.D., Shai, N., Eisenstein, M., Bibi, C., Cohen, N., Hansen, T., Yifrach, E., Harpaz, N., Belostotsky, R., et al.. (2020). A piggybacking mechanism enables peroxisomal localization of the glyoxylate cycle enzyme Mdh2 in yeast. J. Cell Sci. 133: jcs244376, https://doi.org/10.1242/jcs.244376.Search in Google Scholar PubMed PubMed Central

Ganguli, G., Mukherjee, U., and Sonawane, A. (2019). Peroxisomes and oxidative stress: their implications in the modulation of cellular immunity during mycobacterial infection. Front. Microbiol. 10: 1121, https://doi.org/10.3389/fmicb.2019.01121.Search in Google Scholar PubMed PubMed Central

Gatsogiannis, C., Lang, A.E., Meusch, D., Pfaumann, V., Hofnagel, O., Benz, R., Aktories, K., and Raunser, S. (2013). A syringe-like injection mechanism in Photorhabdus luminescens toxins. Nature 495: 520–523, https://doi.org/10.1038/nature11987.Search in Google Scholar PubMed

Gatto, G.J., Geisbrecht, B.V., Gould, S.J., and Berg, J.M. (2000). Peroxisomal targeting signal-1 recognition by the TPR domains of human PEX5. Nat. Struct. Biol. 7: 1091–1095.10.1038/81930Search in Google Scholar PubMed

Gaussmann, S., Gopalswamy, M., Eberhardt, M., Reuter, M., Zou, P., Schliebs, W., Erdmann, R., and Sattler, M. (2021). Membrane interactions of the peroxisomal proteins PEX5 and PEX14. Front. Cell Dev. Biol. 9: 651449, https://doi.org/10.3389/fcell.2021.651449.Search in Google Scholar PubMed PubMed Central

Girzalsky, W., Hoffmann, L.S., Schemenewitz, A., Nolte, A., Kunau, W.-H., and Erdmann, R. (2006). Pex19p-dependent targeting of Pex17p, a peripheral component of the peroxisomal protein import machinery. J. Biol. Chem. 281: 19417–19425, https://doi.org/10.1074/jbc.m603344200.Search in Google Scholar

Gould, S.J., Kalish, J.E., Morrell, J.C., Bjorkman, J., Urquhart, A.J., and Crane, D.I. (1996). Pex13p is an SH3 protein of the peroxisome membrane and a docking factor for the predominantly cytoplasmic PTs1 receptor. J. Cell Biol. 135: 85–95, https://doi.org/10.1083/jcb.135.1.85.Search in Google Scholar PubMed PubMed Central

Gould, S.J., Keller, G.A., Hosken, N., Wilkinson, J., and Subramani, S. (1989). A conserved tripeptide sorts proteins to peroxisomes. J. Cell Biol. 108: 1657–1664, https://doi.org/10.1083/jcb.108.5.1657.Search in Google Scholar PubMed PubMed Central

Gouveia, A.M., Guimaraes, C.P., Oliveira, M.E., Reguenga, C., Sa-Miranda, C., and Azevedo, J.E. (2003). Characterization of the peroxisomal cycling receptor, Pex5p, using a cell-free in vitro import system. J. Biol. Chem. 278: 226–232, https://doi.org/10.1074/jbc.m209498200.Search in Google Scholar PubMed

Gouveia, A.M., Reguenga, C., Oliveira, M.E., Sa-Miranda, C., and Azevedo, J.E. (2000). Characterization of peroxisomal Pex5p from rat liver. Pex5p in the Pex5p-Pex14p membrane complex is a transmembrane protein. J. Biol. Chem. 275: 32444–32451, https://doi.org/10.1074/jbc.m004366200.Search in Google Scholar PubMed

Grimm, I., Saffian, D., Platta, H.W., and Erdmann, R. (2012). The AAA-type ATPases Pex1p and Pex6p and their role in peroxisomal matrix protein import in Saccharomyces cerevisiae. Biochim. Biophys. Acta 1823: 150–158, https://doi.org/10.1016/j.bbamcr.2011.09.005.Search in Google Scholar PubMed

Haanstra, J.R., González-Marcano, E.B., Gualdrón-López, M., and Michels, P.A.M. (2016). Biogenesis, maintenance and dynamics of glycosomes in trypanosomatid parasites. Biochim. Biophys. Acta 1863: 1038–1048, https://doi.org/10.1016/j.bbamcr.2015.09.015.Search in Google Scholar PubMed

Honsho, M., Okumoto, K., Tamura, S., and Fujiki, Y. (2020). Peroxisome biogenesis disorders. Adv. Exp. Med. Biol. 1299: 45–54, https://doi.org/10.1007/978-3-030-60204-8_4.Search in Google Scholar PubMed

Huhse, B., Rehling, P., Albertini, M., Blank, L., Meller, K., and Kunau, W.H. (1998). Pex17p of Saccharomyces cerevisiae is a novel peroxin and component of the peroxisomal protein translocation machinery. J. Cell Biol. 140: 49–60, https://doi.org/10.1083/jcb.140.1.49.Search in Google Scholar PubMed PubMed Central

Imanaka, T. and Shimozawa, N. (Eds.) (2019). Peroxisomes: biogenesis, function, and role in human disease. Springer Singapore, Singapore, Imprint Springer.10.1007/978-981-15-1169-1Search in Google Scholar

Itoh, R. and Fujiki, Y. (2006). Functional domains and dynamic assembly of the peroxin Pex14p, the entry site of matrix proteins. J. Biol. Chem. 281: 10196–10205, https://doi.org/10.1074/jbc.m600158200.Search in Google Scholar PubMed

Jovanovic-Talisman, T. and Zilman, A. (2017). Protein transport by the nuclear pore complex: simple biophysics of a complex biomachine. Biophys. J. 113: 6–14, https://doi.org/10.1016/j.bpj.2017.05.024.Search in Google Scholar PubMed PubMed Central

Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al.. (2021). Highly accurate protein structure prediction with AlphaFold. Nature 596: 583–589, https://doi.org/10.1038/s41586-021-03819-2.Search in Google Scholar PubMed PubMed Central

Kempiński, B., Chełstowska, A., Poznański, J., Król, K., Rymer, Ł., Frydzińska, Z., Girzalsky, W., Skoneczna, A., Erdmann, R., and Skoneczny, M. (2020). The peroxisomal targeting signal 3 (PTS3) of the budding yeast acyl-CoA oxidase is a signal patch. Front. Cell Dev. Biol. 8: 198, https://doi.org/10.3389/fcell.2020.00198.Search in Google Scholar PubMed PubMed Central

Kerssen, D., Hambruch, E., Klaas, W., Platta, H.W., de Kruijff, B., Erdmann, R., Kunau, W.-H., and Schliebs, W. (2006). Membrane association of the cycling peroxisome import receptor Pex5p. J. Biol. Chem. 281: 27003–27015, https://doi.org/10.1074/jbc.m509257200.Search in Google Scholar PubMed

Kleiger, G., Grothe, R., Mallick, P., and Eisenberg, D. (2002). GXXXG and AXXXA: common alpha-helical interaction motifs in proteins, particularly in extremophiles. Biochemistry 41: 5990–5997, https://doi.org/10.1021/bi0200763.Search in Google Scholar PubMed

Klein, A.T.J., van den Berg, M., Bottger, G., Tabak, H.F., and Distel, B. (2002). Saccharomyces cerevisiae acyl-CoA oxidase follows a novel, non-PTS1, import pathway into peroxisomes that is dependent on Pex5p. J. Biol. Chem. 277: 25011–25019, https://doi.org/10.1074/jbc.m203254200.Search in Google Scholar

Knoblach, B., Ishida, R., Hobman, T.C., and Rachubinski, R.A. (2021). Peroxisomes exhibit compromised structure and matrix protein content in SARS-CoV-2-infected cells. Mol. Biol. Cell 32: 1273–1282, https://doi.org/10.1091/mbc.e21-02-0074.Search in Google Scholar PubMed PubMed Central

Krause, C., Rosewich, H., Woehler, A., and Gärtner, J. (2013). Functional analysis of PEX13 mutation in a Zellweger syndrome spectrum patient reveals novel homooligomerization of PEX13 and its role in human peroxisome biogenesis. Hum. Mol. Genet. 22: 3844–3857, https://doi.org/10.1093/hmg/ddt238.Search in Google Scholar PubMed

Kumar, S., Singh, R., Williams, C.P., and van der Klei, I.J. (2016). Stress exposure results in increased peroxisomal levels of yeast Pnc1 and Gpd1, which are imported via a piggy-backing mechanism. Biochim. Biophys. Acta 1863: 148–156, https://doi.org/10.1016/j.bbamcr.2015.10.017.Search in Google Scholar PubMed

Kunze, M. (2020). The type-2 peroxisomal targeting signal. Biochim. Biophys. Acta, Mol. Cell Res. 1867: 118609, https://doi.org/10.1016/j.bbamcr.2019.118609.Search in Google Scholar PubMed

Lanyon-Hogg, T., Warriner, S.L., and Baker, A. (2010). Getting a camel through the eye of a needle: the import of folded proteins by peroxisomes. Biol. Cell 102: 245–263, https://doi.org/10.1042/bc20090159.Search in Google Scholar

Lill, P., Hansen, T., Wendscheck, D., Klink, B.U., Jeziorek, T., Vismpas, D., Miehling, J., Bender, J., Schummer, A., Drepper, F., et al. (2020). Towards the molecular architecture of the peroxisomal receptor docking complex. Proc. Natl. Acad. Sci. U.S.A. 117: 33216–33224, https://doi.org/10.1073/pnas.2009502117.Search in Google Scholar PubMed PubMed Central

McCollum, D., Monosov, E., and Subramani, S. (1993). The pas8 mutant of Pichia pastoris exhibits the peroxisomal protein import deficiencies of Zellweger syndrome cells--the PAS8 protein binds to the COOH-terminal tripeptide peroxisomal targeting signal, and is a member of the TPR protein family. J. Cell Biol. 121: 761–774, https://doi.org/10.1083/jcb.121.4.761.Search in Google Scholar PubMed PubMed Central

McNew, J.A. and Goodman, J.M. (1994). An oligomeric protein is imported into peroxisomes in vivo. J. Cell Biol. 127: 1245–1257, https://doi.org/10.1083/jcb.127.5.1245.Search in Google Scholar PubMed PubMed Central

Meinecke, M., Bartsch, P., and Wagner, R. (2016). Peroxisomal protein import pores. Biochim. Biophys. Acta 1863: 821–827, https://doi.org/10.1016/j.bbamcr.2015.10.013.Search in Google Scholar PubMed

Meinecke, M., Cizmowski, C., Schliebs, W., Krüger, V., Beck, S., Wagner, R., and Erdmann, R. (2010). The peroxisomal importomer constitutes a large and highly dynamic pore. Nat. Cell Biol. 12: 273–277, https://doi.org/10.1038/ncb2027.Search in Google Scholar PubMed

Montilla-Martinez, M., Beck, S., Klümper, J., Meinecke, M., Schliebs, W., Wagner, R., and Erdmann, R. (2015). Distinct pores for peroxisomal import of PTS1 and PTS2 proteins. Cell Rep. 13: 2126–2134, https://doi.org/10.1016/j.celrep.2015.11.016.Search in Google Scholar PubMed

Neufeld, C., Filipp, F.V., Simon, B., Neuhaus, A., Schüller, N., David, C., Kooshapur, H., Madl, T., Erdmann, R., Schliebs, W., et al.. (2009). Structural basis for competitive interactions of Pex14 with the import receptors Pex5 and Pex19. EMBO J. 28: 745–754, https://doi.org/10.1038/emboj.2009.7.Search in Google Scholar PubMed PubMed Central

Neuhaus, A., Eggeling, C., Erdmann, R., and Schliebs, W. (2016). Why do peroxisomes associate with the cytoskeleton? Biochim. Biophys. Acta 1863: 1019–1026, https://doi.org/10.1016/j.bbamcr.2015.11.022.Search in Google Scholar PubMed

Neuhaus, A., Kooshapur, H., Wolf, J., Meyer, N.H., Madl, T., Saidowsky, J., Hambruch, E., Lazam, A., Jung, M., Sattler, M., et al.. (2014). A novel Pex14 protein-interacting site of human Pex5 is critical for matrix protein import into peroxisomes. J. Biol. Chem. 289: 437–448, https://doi.org/10.1074/jbc.m113.499707.Search in Google Scholar PubMed PubMed Central

Niederhoff, K., Meindl-Beinker, N.M., Kerssen, D., Perband, U., Schäfer, A., Schliebs, W., and Kunau, W.-H. (2005). Yeast Pex14p possesses two functionally distinct Pex5p and one Pex7p binding sites. J. Biol. Chem. 280: 35571–35578, https://doi.org/10.1074/jbc.m502460200.Search in Google Scholar PubMed

Nötzel, C., Lingner, T., Klingenberg, H., and Thoms, S. (2016). Identification of new fungal peroxisomal matrix proteins and revision of the PTS1 consensus. Traffic 17: 1110–1124, https://doi.org/10.1111/tra.12426.Search in Google Scholar PubMed

Okumoto, K., El Shermely, M., Natsui, M., Kosako, H., Natsuyama, R., Marutani, T., and Fujiki, Y. (2020). The peroxisome counteracts oxidative stresses by suppressing catalase import via Pex14 phosphorylation. Elife 9: e55896, https://doi.org/10.7554/elife.55896.Search in Google Scholar PubMed PubMed Central

Oliveira, M.E.M., Reguenga, C., Gouveia, A.M.M., Guimarães, C.P., Schliebs, W., Kunau, W.-H., Silva, M.T., Sá-Miranda, C., and Azevedo, J.E. (2002). Mammalian Pex14p: membrane topology and characterisation of the Pex14p-Pex14p interaction. Biochim. Biophys. Acta 1567: 13–22, https://doi.org/10.1016/s0005-2736(02)00635-1.Search in Google Scholar PubMed

Otera, H., Setoguchi, K., Hamasaki, M., Kumashiro, T., Shimizu, N., and Fujiki, Y. (2002). Peroxisomal targeting signal receptor Pex5p interacts with cargoes and import machinery components in a spatiotemporally differentiated manner: conserved Pex5p WXXXF/Y motifs are critical for matrix protein import. Mol. Cell Biol. 22: 1639–1655, https://doi.org/10.1128/mcb.22.6.1639-1655.2002.Search in Google Scholar PubMed PubMed Central

Ozimek, P., Kötter, P., Veenhuis, M., and van der Klei, I.J. (2006). Hansenula polymorpha and Saccharomyces cerevisiae Pex5p’s recognize different, independent peroxisomal targeting signals in alcohol oxidase. FEBS Lett. 580: 46–50, https://doi.org/10.1016/j.febslet.2005.11.045.Search in Google Scholar PubMed

Pires, J.R., Hong, X., Brockmann, C., Volkmer-Engert, R., Schneider-Mergener, J., Oschkinat, H., and Erdmann, R. (2003). The ScPex13p SH3 domain exposes two distinct binding sites for Pex5p and Pex14p. J. Mol. Biol. 326: 1427–1435, https://doi.org/10.1016/s0022-2836(03)00039-1.Search in Google Scholar PubMed

Platta, H.W., El Magraoui, F., Schlee, D., Grunau, S., Girzalsky, W., and Erdmann, R. (2007). Ubiquitination of the peroxisomal import receptor Pex5p is required for its recycling. J. Cell Biol. 177: 197–204, https://doi.org/10.1083/jcb.200611012.Search in Google Scholar PubMed PubMed Central

Platta, H.W., Girzalsky, W., and Erdmann, R. (2004). Ubiquitination of the peroxisomal import receptor Pex5p. Biochem. J. 384: 37–45, https://doi.org/10.1042/bj20040572.Search in Google Scholar

Purdue, P.E., Yang, X., and Lazarow, P.B. (1998). Pex18p and Pex21p, a novel pair of related peroxins essential for peroxisomal targeting by the PTS2 pathway. J. Cell Biol. 143: 1859–1869, https://doi.org/10.1083/jcb.143.7.1859.Search in Google Scholar PubMed PubMed Central

Rayapuram, N. and Subramani, S. (2006). The importomer--a peroxisomal membrane complex involved in protein translocation into the peroxisome matrix. Biochim. Biophys. Acta 1763: 1613–1619, https://doi.org/10.1016/j.bbamcr.2006.08.035.Search in Google Scholar PubMed

Reuter, M., Kooshapur, H., Suda, J.-G., Gaussmann, S., Neuhaus, A., Brühl, L., Bharti, P., Jung, M., Schliebs, W., Sattler, M., et al.. (2021). Competitive microtubule binding of PEX14 coordinates peroxisomal protein import and motility. J. Mol. Biol. 433: 166765, https://doi.org/10.1016/j.jmb.2020.166765.Search in Google Scholar PubMed

Rudowitz, M., Erdmann, R., and Schliebs, W. (2020). Membrane processing and steady-state regulation of the alternative peroxisomal import receptor Pex9p. Front. Cell Dev. Biol. 8: 566321, https://doi.org/10.3389/fcell.2020.566321.Search in Google Scholar PubMed PubMed Central

Rymer, Ł., Kempiński, B., Chełstowska, A., and Skoneczny, M. (2018). The budding yeast Pex5p receptor directs Fox2p and Cta1p into peroxisomes via its N-terminal region near the FxxxW domain. J. Cell Sci. 131: jcs216986.10.1242/jcs.216986Search in Google Scholar PubMed

Sacksteder, K.A., Jones, J.M., South, S.T., Li, X., Liu, Y., and Gould, S.J. (2000). PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis. J. Cell Biol. 148: 931–944, https://doi.org/10.1083/jcb.148.5.931.Search in Google Scholar PubMed PubMed Central

Saryi, N.A.A., Hutchinson, J.D., Al-Hejjaj, M.Y., Sedelnikova, S., Baker, P., and Hettema, E.H. (2017). Pnc1 piggy-back import into peroxisomes relies on Gpd1 homodimerisation. Sci. Rep. 7: 42579, https://doi.org/10.1038/srep42579.Search in Google Scholar PubMed PubMed Central

Schell-Steven, A., Stein, K., Amoros, M., Landgraf, C., Volkmer-Engert, R., Rottensteiner, H., and Erdmann, R. (2005). Identification of a novel, intraperoxisomal pex14-binding site in pex13: association of pex13 with the docking complex is essential for peroxisomal matrix protein import. Mol. Cell Biol. 25: 3007–3018, https://doi.org/10.1128/mcb.25.8.3007-3018.2005.Search in Google Scholar PubMed PubMed Central

Schliebs, W., Girzalsky, W., and Erdmann, R. (2010). Peroxisomal protein import and ERAD: variations on a common theme. Nat. Rev. Mol. Cell Biol. 11: 885–890, https://doi.org/10.1038/nrm3008.Search in Google Scholar PubMed

Schliebs, W., Saidowsky, J., Agianian, B., Dodt, G., Herberg, F.W., and Kunau, W.H. (1999). Recombinant human peroxisomal targeting signal receptor PEX5. Structural basis for interaction of PEX5 with PEX14. J. Biol. Chem. 274: 5666–5673, https://doi.org/10.1074/jbc.274.9.5666.Search in Google Scholar PubMed

Schummer, A., Maier, R., Gabay-Maskit, S., Hansen, T., Mühlhäuser, W.W.D., Suppanz, I., Fadel, A., Schuldiner, M., Girzalsky, W., Oeljeklaus, S., et al.. (2020). Pex14p phosphorylation modulates import of citrate synthase 2 into peroxisomes in Saccharomyces cerevisiae. Front Cell. Dev. Biol. 8, https://doi.org/10.3389/fcell.2020.549451.Search in Google Scholar PubMed PubMed Central

Schwerter, D.P., Grimm, I., Platta, H.W., and Erdmann, R. (2017). ATP-driven processes of peroxisomal matrix protein import. Biol. Chem. 398: 607–624, https://doi.org/10.1515/hsz-2016-0293.Search in Google Scholar PubMed

Shimizu, N., Itoh, R., Hirono, Y., Otera, H., Ghaedi, K., Tateishi, K., Tamura, S., Okumoto, K., Harano, T., Mukai, S., et al.. (1999). The peroxin Pex14p. cDNA cloning by functional complementation on a Chinese hamster ovary cell mutant, characterization, and functional analysis. J. Biol. Chem. 274: 12593–12604, https://doi.org/10.1074/jbc.274.18.12593.Search in Google Scholar PubMed

Skowyra, M.L. and Rapoport, T.A. (2022). PEX5 translocation into and out of peroxisomes drives matrix protein import. Mol. Cell, https://doi.org/10.1016/j.molcel.2022.07.004 (Epub ahead of print).Search in Google Scholar PubMed PubMed Central

Smith, J.J., Szilard, R.K., Marelli, M., and Rachubinski, R.A. (1997). The peroxin Pex17p of the yeast Yarrowia lipolytica is associated peripherally with the peroxisomal membrane and is required for the import of a subset of matrix proteins. Mol. Cell Biol. 17: 2511–2520, https://doi.org/10.1128/mcb.17.5.2511.Search in Google Scholar

Stelter, P., Kunze, R., Flemming, D., Höpfner, D., Diepholz, M., Philippsen, P., Böttcher, B., and Hurt, E. (2007). Molecular basis for the functional interaction of dynein light chain with the nuclear-pore complex. Nat. Cell Biol. 9: 788–796, https://doi.org/10.1038/ncb1604.Search in Google Scholar PubMed

Su, J.-R., Takeda, K., Tamura, S., Fujiki, Y., and Miki, K. (2009). Crystal structure of the conserved N-terminal domain of the peroxisomal matrix protein import receptor, Pex14p. Proc. Natl. Acad. Sci. U.S.A. 106: 417–421, https://doi.org/10.1073/pnas.0808681106.Search in Google Scholar PubMed PubMed Central

Swinkels, B.W., Gould, S.J., Bodnar, A.G., Rachubinski, R.A., and Subramani, S. (1991). A novel, cleavable peroxisomal targeting signal at the amino-terminus of the rat 3-ketoacyl-CoA thiolase. EMBO J. 10: 3255–3262, https://doi.org/10.1002/j.1460-2075.1991.tb04889.x.Search in Google Scholar PubMed PubMed Central

Tan, D., Blok, N.B., Rapoport, T.A., and Walz, T. (2016). Structures of the double-ring AAA ATPase Pex1-Pex6 involved in peroxisome biogenesis. FEBS J. 283: 986–992, https://doi.org/10.1111/febs.13569.Search in Google Scholar PubMed PubMed Central

Tolbert, N.E. (1971). Microbodies-peroxisomes and glyoxysomes. Annu. Rev. Plant Physiol. 22: 45–74, https://doi.org/10.1146/annurev.pp.22.060171.000401.Search in Google Scholar

Urquhart, A.J., Kennedy, D., Gould, S.J., and Crane, D.I. (2000). Interaction of Pex5p, the type 1 peroxisome targeting signal receptor, with the peroxisomal membrane proteins Pex14p and Pex13p. J. Biol. Chem. 275: 4127–4136, https://doi.org/10.1074/jbc.275.6.4127.Search in Google Scholar PubMed

van den Bosch, H., Schutgens, R.B., Wanders, R.J., and Tager, J.M. (1992). Biochemistry of peroxisomes. Annu. Rev. Biochem. 61: 157–197, https://doi.org/10.1146/annurev.bi.61.070192.001105.Search in Google Scholar PubMed

Varadi, M., Anyango, S., Deshpande, M., Nair, S., Natassia, C., Yordanova, G., Yuan, D., Stroe, O., Wood, G., Laydon, A., et al.. (2022). AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 50: D439–D444, https://doi.org/10.1093/nar/gkab1061.Search in Google Scholar PubMed PubMed Central

Veenhuis, M., van Dijken, J.P., and Harder, W. (1976). Cytochemical studies on the localization of methanol oxidase and other oxidases in peroxisomes of methanol-grown Hansenula polymorpha. Arch. Microbiol. 111: 123–135, https://doi.org/10.1007/bf00446559.Search in Google Scholar

Walton, P.A., Gould, S.J., Feramisco, J.R., and Subramani, S. (1992). Transport of microinjected proteins into peroxisomes of mammalian cells: inability of Zellweger cell lines to import proteins with the SKL tripeptide peroxisomal targeting signal. Mol. Cell Biol. 12: 531–541, https://doi.org/10.1128/mcb.12.2.531-541.1992.Search in Google Scholar PubMed PubMed Central

Walton, P.A., Hill, P.E., and Subramani, S. (1995). Import of stably folded proteins into peroxisomes. Mol. Biol. Cell 6: 675–683, https://doi.org/10.1091/mbc.6.6.675.Search in Google Scholar PubMed PubMed Central

Wanders, R.J.A. and Waterham, H.R. (2005). Peroxisomal disorders I: biochemistry and genetics of peroxisome biogenesis disorders. Clin. Genet. 67: 107–133, https://doi.org/10.1111/j.1399-0004.2004.00329.x.Search in Google Scholar PubMed

Wang, M., Weiss, M., Simonovic, M., Haertinger, G., Schrimpf, S.P., Hengartner, M.O., and von Mering, C. (2012). PaxDb, a database of protein abundance averages across all three domains of life. Mol. Cell. Proteomics 11: 492–500, https://doi.org/10.1074/mcp.o111.014704.Search in Google Scholar

Waterham, H.R. and Ebberink, M.S. (2012). Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim. Biophys. Acta 1822: 1430–1441, https://doi.org/10.1016/j.bbadis.2012.04.006.Search in Google Scholar PubMed

Williams, C. and Distel, B. (2006). Pex13p: docking or cargo handling protein? Biochim. Biophys. Acta 1763: 1585–1591, https://doi.org/10.1016/j.bbamcr.2006.09.007.Search in Google Scholar PubMed

Williams, C., van den Berg, M., and Distel, B. (2005). Saccharomyces cerevisiae Pex14p contains two independent Pex5p binding sites, which are both essential for PTS1 protein import. FEBS Lett. 579: 3416–3420, https://doi.org/10.1016/j.febslet.2005.05.011.Search in Google Scholar PubMed

Yamashita, K., Tamura, S., Honsho, M., Yada, H., Yagita, Y., Kosako, H., and Fujiki, Y. (2020). Mitotic phosphorylation of Pex14p regulates peroxisomal import machinery. J. Cell Biol. 219, https://doi.org/10.1083/jcb.202001003.Search in Google Scholar PubMed PubMed Central

Yang, J., Pieuchot, L., and Jedd, G. (2018). Artificial import substrates reveal an omnivorous peroxisomal importomer. Traffic 19: 786–797, https://doi.org/10.1111/tra.12607.Search in Google Scholar PubMed

Yifrach, E., Chuartzman, S.G., Dahan, N., Maskit, S., Zada, L., Weill, U., Yofe, I., Olender, T., Schuldiner, M., and Zalckvar, E. (2016). Characterization of proteome dynamics during growth in oleate reveals a new peroxisome-targeting receptor. J. Cell Sci. 129: 4067–4075.10.1242/jcs.195255Search in Google Scholar

Zeytuni, N. and Zarivach, R. (2012). Structural and functional discussion of the tetra-trico-peptide repeat, a protein interaction module. Structure 20: 397–405, https://doi.org/10.1016/j.str.2012.01.006.Search in Google Scholar PubMed

Received: 2022-04-14

Accepted: 2022-08-25

Published Online: 2022-09-20

Published in Print: 2023-02-23

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

https://doi.org/10.1515/hsz-2022-0161

Keywords for this article

docking complex; peroxins; peroxisomal biogenesis; peroxisomal import; peroxisomal translocon

Creative Commons

BY 4.0