Dynamic and Functional Assembly of the AAA Peroxins, Pex1p and Pex6p, and Their Membrane Receptor Pex26p

Tamura, Shigehiko; Yasutake, Shinobu; Matsumoto, Naomi; Fujiki, Yukio

doi:10.1074/jbc.m605159200

Cited by 53 publications

(89 citation statements)

References 41 publications

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“…PEX1 and PEX6 each contain two AAA domains and hetero-oligomerize. PEX26 recruits the AAA complex to the peroxisome by binding to the N terminus of PEX6 (20). Motion of the PEX1-PEX6 complex Table 2.…”

Section: Discussionmentioning

confidence: 99%

“…recycles monoubiquitinated PEX5 from the peroxisome membrane to the cytosol. The different nucleotide states of PEX6 affect its binding and release from PEX26 (20). Considering the multiple conformational states of the PEX1-PEX6-PEX26 complex, there should be several opportunities to influence folding intermediates in patients with missense changes in these proteins.…”

Section: Discussionmentioning

confidence: 99%

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Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule compounds

Zhang

Chen

Jiralerspong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Zellweger spectrum disorder (ZSD) is a heterogeneous group of diseases with high morbidity and mortality caused by failure to assemble normal peroxisomes. There is no therapy for ZSD, but management is supportive. Nevertheless, one-half of the patients have a phenotype milder than classic Zellweger syndrome and exhibit a progressive disease course. Thus, patients would benefit if therapies became available and were instituted early. Recent reports indicate several interventions that result in partial peroxisome recovery in ZSD fibroblasts. To identify drugs that recover peroxisome functions, we expressed a GFP-peroxisome targeting signal 1 reporter in fibroblasts containing the common disease allele, PEX1-p.Gly843Asp. The GFP reporter remained cytosolic at baseline, and improvement in peroxisome functions was detected by the redistribution of the GFP reporter from the cytosol to the peroxisome. We established a high-content screening assay based on this phenotype assay and evaluated 2,080 small molecules. The cells were cultured in chemical for 2 days and then, were fixed and imaged by epifluorescent microscopy on a high-content imaging platform. We identified four compounds that partially recover matrix protein import, and we confirmed three using independent assays. Our results suggest that PEX1-p.G843D is a misfolded protein amenable to chaperone therapy.Zellweger spectrum | AAA ATPase | misfolded protein | chemical screening | pharmacologic chaperone

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule compounds

Zhang

Chen

Jiralerspong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The AAA-ATPases, PEX1 and PEX6, constitute hetero-oligomers that function in yeast (Faber et al, 1998) and mammalian cells (Geisbrecht et al, 1998;Tamura et al, 2006). To examine whether PEX1 and PEX6 are able to interact in plant cells, we produced a cYFP-PEX1 fusion construct for use in a BiFC assay.…”

Section: Protein-protein Interactions Among Apem9 Pex6 and Pex1mentioning

confidence: 99%

“…An absence of PEX1 or PEX6 causes accumulation of PEX5 (the PTS1 receptor) in the peroxisomal membranes in yeast cells (Kiel et al, 2005), indicating that these AAA-ATPases export PEX5 back to the cytosol after its cargo is released into the peroxisomal matrix. In yeast and mammalian cells, these AAA-ATPases are known to be essential for peroxisomal functions (Platta et al, 2005;Tamura et al, 2006). In plants, the homologs of both PEX1 and PEX6 have been identified, and knockdown mutants, pex1i and pex6i, were shown to exhibit defects in peroxisomal protein transport (Zolman and Bartel, 2004;Nito et al, 2007).…”

Section: Apem9 Tethers the Aaa-atpase Complex To Peroxisomal Membranesmentioning

confidence: 99%

ArabidopsisABERRANT PEROXISOME MORPHOLOGY9 Is a Peroxin That Recruits the PEX1-PEX6 Complex to Peroxisomes

et al. 2011

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Peroxisomes have pivotal roles in several metabolic processes, such as the detoxification of H 2 O 2 and b-oxidation of fatty acids, and their functions are tightly regulated by multiple factors involved in peroxisome biogenesis, including protein transport. This study describes the isolation of an embryonic lethal Arabidopsis thaliana mutant, aberrant peroxisome morphology9 (apem9), which is compromised in protein transport into peroxisomes. The APEM9 gene was found to encode an unknown protein. Compared with apem9 having the nucleotide substitution, the knockdown mutants showed severe defects in peroxisomal functions and plant growth. We showed that expression of APEM9 altered PEROXIN6 (PEX6) subcellular localization from the cytosol to peroxisomes. In addition, we showed that PEX1 and PEX6 comprise a heterooligomer and that this complex was recruited to peroxisomal membranes via protein-protein interactions of APEM9 with PEX6. These findings show that APEM9 functions as an anchoring protein, similar to Pex26 in mammals and Pex15p in yeast. Interestingly, however, the identities of amino acids among these anchoring proteins are quite low. These results indicate that although the association of the PEX1-PEX6 complex with peroxisomal membranes is essential for peroxisomal functions, the protein that anchors this complex evolved uniquely in plants.

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“…The PEX1-PEX6 interaction in yeast and humans requires the PEX1 D2 and D1 regions (Birschmann et al, 2005;Tamura et al, 2006). In addition to supporting heterohexamer assembly, ATP hydrolysis elicits conformational changes in the PEX1-PEX6 complex that facilitate the retrotranslocation of ubiquitinated PEX5 in yeast (for review, see Platta et al, 2016) and humans (Tamura et al, 2006).…”

mentioning

confidence: 99%

The PEX1 ATPase Stabilizes PEX6 and Plays Essential Roles in Peroxisome Biology

et al. 2017

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A variety of metabolic pathways are sequestered in peroxisomes, conserved organelles that are essential for human and plant survival. Peroxin (PEX) proteins generate and maintain peroxisomes. The PEX1 ATPase facilitates recycling of the peroxisome matrix protein receptor PEX5 and is the most commonly affected peroxin in human peroxisome biogenesis disorders. Here, we describe the isolation and characterization of, to our knowledge, the first Arabidopsis (Arabidopsis thaliana) pex1 missense alleles: pex1-2 and pex1-3. pex1-2 displayed peroxisome-related defects accompanied by reduced PEX1 and PEX6 levels. These pex1-2 defects were exacerbated by growth at high temperature and ameliorated by growth at low temperature or by PEX6 overexpression, suggesting that PEX1 enhances PEX6 stability and vice versa. pex1-3 conferred embryo lethality when homozygous, confirming that PEX1, like several other Arabidopsis peroxins, is essential for embryogenesis. pex1-3 displayed symptoms of peroxisome dysfunction when heterozygous; this semidominance is consistent with PEX1 forming a heterooligomer with PEX6 that is poisoned by pex1-3 subunits. Blocking autophagy partially rescued PEX1/pex1-3 defects, including the restoration of normal peroxisome size, suggesting that increasing peroxisome abundance can compensate for the deficiencies caused by pex1-3 and that the enlarged peroxisomes visible in PEX1/pex1-3 may represent autophagy intermediates. Overexpressing PEX1 in wild-type plants impaired growth, suggesting that excessive PEX1 can be detrimental. Our genetic, molecular, and physiological data support the heterohexamer model of PEX1-PEX6 function in plants.

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Dynamic and Functional Assembly of the AAA Peroxins, Pex1p and Pex6p, and Their Membrane Receptor Pex26p

Cited by 53 publications

References 41 publications

Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule compounds

Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule compounds

ArabidopsisABERRANT PEROXISOME MORPHOLOGY9 Is a Peroxin That Recruits the PEX1-PEX6 Complex to Peroxisomes

The PEX1 ATPase Stabilizes PEX6 and Plays Essential Roles in Peroxisome Biology

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