The peroxisomal AAA-ATPase Pex1/Pex6 unfolds substrates by processive threading

Gardner, Brooke M.; Castanzo, Dominic T; Chowdhury, Saikat; Stjepanović, Goran; Stefely, Matthew S.; Hurley, James H.; Lander, Gabriel C.; Martin, Andreas

doi:10.1038/s41467-017-02474-4

Cited by 53 publications

(114 citation statements)

References 81 publications

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“…Here we show that the Pex1p-Pex6p complex directly interacts with monoubiquitinated Pex5p in vitro. In line with recently published results, we found no direct interaction with unmodified Pex5p (67). This is in contrast to mammalian Pex1p, which exists as a homo-oligomer in the cytosol and a hetero-oligomer with Pex6p on peroxisome membranes (68).…”

Section: Ubiquitin-dependent Receptor Recognition Mediated By Pex1psupporting

confidence: 90%

Receptor recognition by the peroxisomal AAA complex depends on the presence of the ubiquitin moiety and is mediated by Pex1p

Schwerter

Grimm

Girzalsky

et al. 2018

Journal of Biological Chemistry

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The receptor cycle of type I peroxisomal matrix protein import is completed by ubiquitination of the membrane-bound peroxisome biogenesis factor 5 (Pex5p) and its subsequent export back to the cytosol. The receptor export is the only ATP-dependent step of the whole process and is facilitated by two members of the AAA family of proteins (ATPases associated with various cellular activities), namely Pex1p and Pex6p. To gain further insight into substrate recognition by the AAA complex, we generated an N-terminally linked ubiquitin-Pex5p fusion protein. This fusion protein displayed biological activity because it is able to functionally complement a PEX5-deletion in assays revealed its interaction at WT level with the native cargo protein Pcs60p and Pex14p, a constituent of the receptor docking complex. We also demonstrate deubiquitination by the deubiquitinating enzyme Ubp15p. pulldown assays and cross-linking studies demonstrate that Pex5p recognition by the AAA complex depends on the presence of the ubiquitin moiety and is mediated by Pex1p.

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Section: Ubiquitin-dependent Receptor Recognition Mediated By Pex1psupporting

confidence: 90%

Receptor recognition by the peroxisomal AAA complex depends on the presence of the ubiquitin moiety and is mediated by Pex1p

Schwerter

Grimm

Girzalsky

et al. 2018

Journal of Biological Chemistry

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“…1 , 2 ). Very recently, it was shown that the AAA–ATPase Pex1/Pex6 unfolds substrates by processive threading (Gardner et al 2018 ), and that monoubiquitinated Pex5, which interacts with the AAA–ATPases Pex1 and Pex6, is unfolded during its dislocation to the cytosol (Pedrosa et al 2018 ).…”

Section: Mysterious Machinery: New Proteins and Functions At The Peromentioning

confidence: 99%

The peroxisome: an update on mysteries 2.0

Islinger

Voelkl

Fahimi

et al. 2018

Histochem Cell Biol

234

227

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Peroxisomes are key metabolic organelles, which contribute to cellular lipid metabolism, e.g. the β-oxidation of fatty acids and the synthesis of myelin sheath lipids, as well as cellular redox balance. Peroxisomal dysfunction has been linked to severe metabolic disorders in man, but peroxisomes are now also recognized as protective organelles with a wider significance in human health and potential impact on a large number of globally important human diseases such as neurodegeneration, obesity, cancer, and age-related disorders. Therefore, the interest in peroxisomes and their physiological functions has significantly increased in recent years. In this review, we intend to highlight recent discoveries, advancements and trends in peroxisome research, and present an update as well as a continuation of two former review articles addressing the unsolved mysteries of this astonishing organelle. We summarize novel findings on the biological functions of peroxisomes, their biogenesis, formation, membrane dynamics and division, as well as on peroxisome–organelle contacts and cooperation. Furthermore, novel peroxisomal proteins and machineries at the peroxisomal membrane are discussed. Finally, we address recent findings on the role of peroxisomes in the brain, in neurological disorders, and in the development of cancer.

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“…(a) the shuttling receptors/transporters, which in most organisms, including mammals, are PEX5, for PTS1 proteins, and the PEX5-PEX7 complex for PTS2 proteins [9][10][11][12]; (b) the docking/translocation module (DTM), a peroxisomal transmembrane protein complex comprising the core components PEX13 and PEX14 and the RING finger proteins PEX2, PEX10 and PEX12 [13,14]; (c) the receptor export module (REM), a complex comprising PEX1 and PEX6, two ATPases belonging to the AAA (ATPases associated with diverse cellular activities) family, and a poorly conserved peroxisomal membrane anchor protein which receives different names in different organisms (i.e., PEX26 in mammals, PEX15 in some yeasts and fungi, and APEM9 in plants) [15][16][17]; and lastly, (d) a group of proteins involved in ubiquitination/deubiquitination events, namely the ubiquitin-activating enzyme and ubiquitin as well as ubiquitinconjugating enzymes (e.g., E2D1/2/3 in mammals or the PEX4.PEX22 complex in yeasts and plants) and a deubiquitinase [18][19][20][21][22].…”

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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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.

show abstract

The peroxisomal AAA-ATPase Pex1/Pex6 unfolds substrates by processive threading

Cited by 53 publications

References 81 publications

Receptor recognition by the peroxisomal AAA complex depends on the presence of the ubiquitin moiety and is mediated by Pex1p

Receptor recognition by the peroxisomal AAA complex depends on the presence of the ubiquitin moiety and is mediated by Pex1p

The peroxisome: an update on mysteries 2.0

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

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