Protein transport into peroxisomes: Knowns and unknowns

Francisco, Tânia; Rodrigues, Tony A.; Dias, Ana Cristina; Barros‐Barbosa, Aurora; Bicho, Diana; Azevedo, Jorge E.

doi:10.1002/bies.201700047

Cited by 66 publications

(62 citation statements)

References 124 publications

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“…The first is that both PEX13 and PEX14 possess PEX5-interacting domains on both sides of the peroxisomal membrane. This lends support to the idea that the two peroxins are key components of the transmembrane hydrophilic channel into which PEX5 becomes inserted to release its cargoes into the organelle matrix [5,74]. The second regards the fact that the cytosolexposed PEX5-binding sites present in both PEX13 and PEX14 are located in regions of these two proteins predicted to be intrinsically disordered.…”

Section: Discussionsupporting

confidence: 54%

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Membrane topologies of PEX13 and PEX14 provide new insights on the mechanism of protein import into peroxisomes

et al. 2018

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PEX13 and PEX14 are two core components of the so‐called peroxisomal docking/translocation module, the transmembrane hydrophilic channel through which newly synthesized peroxisomal proteins are translocated into the organelle matrix. The two proteins interact with each other and with PEX5, the peroxisomal matrix protein shuttling receptor, through relatively well characterized domains. However, the topologies of these membrane proteins are still poorly defined. Here, we subjected proteoliposomes containing PEX13 or PEX14 and purified rat liver peroxisomes to protease‐protection assays and analyzed the protected protein fragments by mass spectrometry, Edman degradation and western blotting using antibodies directed to specific domains of the proteins. Our results indicate that PEX14 is a bona fide intrinsic membrane protein with a Nin‐Cout topology, and that PEX13 adopts a Nout‐Cin topology, thus exposing its carboxy‐terminal Src homology 3 [SH3] domain into the organelle matrix. These results reconcile several enigmatic findings previously reported on PEX13 and PEX14 and provide new insights into the organization of the peroxisomal protein import machinery. Enzymes Trypsin, http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/4/21/4.html; Proteinase K, http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/4/21/64.html; Tobacco etch virus protease, http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/4/22/44.html.

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Section: Discussionsupporting

confidence: 54%

“…The machinery that transports these proteins to the peroxisome matrix comprises many different components [4][5][6][7]. Most are exclusively dedicated to this taskthese belong to the so-called peroxin family [8].…”

Section: Introductionmentioning

confidence: 99%

Membrane topologies of PEX13 and PEX14 provide new insights on the mechanism of protein import into peroxisomes

et al. 2018

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“…This suggests that binding of a cargo protein by PEX5 is not accompanied by a global disorder-to-order transition in the N-terminal half of PEX5, a property that may have functional implications not only at the level of the PEX5-cargo protein complex but also later in the pathway, when the receptor-cargo protein complex interacts with the DTM (see below). For instance, as suggested recently [93], this PEX5 domain may behave as an entropic bristle [105], sweeping out other proteins from the vicinity of the cargo protein it binds, thus explaining the inhibitory effect of PEX5 on cargo oligomerization. However, it should be noted that this is not the only mechanism behind the chaperone/holdase function of PEX5, because the N-terminal half of PEX5 also interacts directly with cargo proteins [78,79,82].…”

Section: The Pex5-cargo Protein Interactionmentioning

confidence: 80%

“…The molecular basis for the allosteric mechanism controlling the DTM-binding capacity of the N-terminal half of PEX5 is still unknown. As mentioned above, it is possible that the N-terminal half of PEX5 interacts with the TPR domain via a still unidentified SLiM/MoRF/PSE, and that this interaction is no longer favored when a PTS1 protein binds to the TPR domain, thus releasing the N-terminal half of PEX5 from the inhibitory action of the TPR domain [93,94]. The finding that recombinant proteins comprising each of these two domains of PEX5 can interact in vitro favors such a possibility [95].…”

Section: Introductionmentioning

confidence: 99%

The intrinsically disordered nature of the peroxisomal protein translocation machinery

et al. 2018

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Despite having a membrane that is impermeable to all but the smallest of metabolites, peroxisomes acquire their newly synthesized (cytosolic) matrix proteins in an already folded conformation. In some cases, even oligomeric proteins have been reported to translocate the organelle membrane. The protein sorting machinery that accomplishes this feat must be rather flexible and, unsurprisingly, several of its key components have large intrinsically disordered domains. Here, we provide an overview on these domains and their interactions trying to infer their functional roles in this protein sorting pathway.

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“…3A). Peroxisomes import matrix proteins from the cytosol via dedicated 394 import machinery at the peroxisomal membrane (Francisco et al 2017). Matrix proteins such as catalase 395 are imported into peroxisomes via a C-terminal peroxisomal targeting signal (PTS1).…”

Section: Protein Import Into Mff-deficient Peroxisomes Is Impaired Inmentioning

confidence: 99%

Mitochondrial fission factor (MFF) is a critical regulator of peroxisome maturation

Passmore

Godinho

Ferdinandusse

et al. 2020

Preprint

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AbstractPeroxisomes are highly dynamic subcellular compartments with important functions in lipid and ROS metabolism. Impaired peroxisomal function can lead to severe metabolic disorders with developmental defects and neurological abnormalities. Recently, a new group of disorders has been identified, characterised by defects in the membrane dynamics and division of peroxisomes rather than by loss of metabolic functions. However, the contribution of impaired peroxisome plasticity to the pathophysiology of those disorders is not well understood. Mitochondrial fission factor (MFF) is a key component of both the peroxisomal and mitochondrial division machinery. Patients with MFF deficiency present with developmental and neurological abnormalities. Peroxisomes (and mitochondria) in patient fibroblasts are highly elongated as a result of impaired organelle division. The majority of studies into MFF-deficiency have focused on mitochondrial dysfunction, but the contribution of peroxisomal alterations to the pathophysiology is largely unknown. Here, we show that MFF deficiency does not cause alterations to overall peroxisomal biochemical function. However, loss of MFF results in reduced import-competency of the peroxisomal compartment and leads to the accumulation of pre-peroxisomal membrane structures. We show that peroxisomes in MFF-deficient cells display alterations in peroxisomal redox state and intra-peroxisomal pH. Removal of elongated peroxisomes through induction of autophagic processes is not impaired. A mathematical model describing key processes involved in peroxisome dynamics sheds further light into the physical processes disturbed in MFF-deficient cells. The consequences of our findings for the pathophysiology of MFF-deficiency and related disorders with impaired peroxisome plasticity are discussed.

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Protein transport into peroxisomes: Knowns and unknowns

Cited by 66 publications

References 124 publications

Membrane topologies of PEX13 and PEX14 provide new insights on the mechanism of protein import into peroxisomes

Membrane topologies of PEX13 and PEX14 provide new insights on the mechanism of protein import into peroxisomes

The intrinsically disordered nature of the peroxisomal protein translocation machinery

Mitochondrial fission factor (MFF) is a critical regulator of peroxisome maturation

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