Structure of the peroxisomal Pex1/Pex6 ATPase complex bound to a substrate

Rüttermann, Maximilian; Koci, Michelle; Lill, Pascal; Geladas, Ermis Dionysios; Kaschani, Farnusch; Klink, Björn Udo; Erdmann, Ralf; Gatsogiannis, Christos

doi:10.1038/s41467-023-41640-9

Cited by 3 publications

(2 citation statements)

References 99 publications

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“…Very recently, data about the first high-resolution cryo-EM structures of the Pex1/Pex6 complex from S. cerevisiae were presented including two different conformations bound to an endogenous substrate. Rüttermann et al showed that translocation of the substrate occurs along the central pore formed by rings D1 and D2; however, ATP hydrolysis is restricted in the ring D2 (Rüttermann et al 2023 ). The pore II loops of the Pex1/Pex6 (D2) subdomains bind the substrate in a canonical staircase arrangement (Puchades et al 2020 ), but Pex1 and Pex6 function in pairs.…”

Section: Some Mysteries About Peroxisomal Matrix Protein Import Discl...mentioning

confidence: 99%

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The peroxisome: an update on mysteries 3.0

Kumar,

Islinger,

Worthy

et al. 2024

Histochem Cell Biol

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Peroxisomes are highly dynamic, oxidative organelles with key metabolic functions in cellular lipid metabolism, such as the β-oxidation of fatty acids and the synthesis of myelin sheath lipids, as well as the regulation of cellular redox balance. Loss of peroxisomal functions causes severe metabolic disorders in humans. Furthermore, peroxisomes also fulfil protective roles in pathogen and viral defence and immunity, highlighting their wider significance in human health and disease. This has sparked increasing interest in peroxisome biology and their physiological functions. This review presents an update and a continuation of three previous review articles addressing the unsolved mysteries of this remarkable organelle. We continue to highlight recent discoveries, advancements, and trends in peroxisome research, and address novel findings on the metabolic functions of peroxisomes, their biogenesis, protein import, membrane dynamics and division, as well as on peroxisome–organelle membrane contact sites and organelle cooperation. Furthermore, recent insights into peroxisome organisation through super-resolution microscopy are discussed. Finally, we address new roles for peroxisomes in immune and defence mechanisms and in human disorders, and for peroxisomal functions in different cell/tissue types, in particular their contribution to organ-specific pathologies.

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Section: Some Mysteries About Peroxisomal Matrix Protein Import Discl...mentioning

confidence: 99%

“…The ATPase cycle involves uncoupling of a “twin seam” Pex1/Pex6 (D2) heterodimer from the staircase. The respective mechanical forces are transmitted to the D1 ring via different interfaces, resulting in alternate widening and constriction of its pore (Rüttermann et al 2023 ).…”

Section: Some Mysteries About Peroxisomal Matrix Protein Import Discl...mentioning

confidence: 99%

The peroxisome: an update on mysteries 3.0

Kumar,

Islinger,

Worthy

et al. 2024

Histochem Cell Biol

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PEX1^G843Dremains functional in peroxisome biogenesis but is rapidly degraded by the proteasome

Sheedy,

Chowdhury,

Ali

et al. 2024

Preprint

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The PEX1/PEX6 AAA-ATPase is required for the biogenesis and maintenance of peroxisomes. Mutations inHsPEX1 andHsPEX6 disrupt peroxisomal matrix protein import and are the leading cause of Peroxisome Biogenesis Disorders (PBDs). The most common disease-causing mutation in PEX1 is theHsPEX1G843Dallele, which results in a reduction of peroxisomal protein import. Here we demonstrate thatin vitrothe homologous yeast mutant,ScPex1G700D, reduces the stability of Pex1's active D2 ATPase domain and impairs assembly with Pex6, but can still form an active AAA-ATPase motor.In vivo,ScPex1G700Dexhibits only a slight defect in peroxisome import. We generated model humanHsPEX1G843Dcell lines and show that PEX1G843Dis rapidly degraded by the proteasome, but that induced overexpression of PEX1G843Dcan restore peroxisome import. Additionally, we found that the G843D mutation reduces PEX1's affinity for PEX6, and that impaired assembly is sufficient to induce degradation of PEX1WT. Lastly, we found that fusing a deubiquitinase to PEX1G843Dsignificantly hinders its degradation in mammalian cells. Altogether, our findings suggest a novel regulatory mechanism for PEX1/PEX6 hexamer assembly and highlight the potential of protein stabilization as a therapeutic strategy for PBDs arising from the G843D mutation and other PEX1 hypomorphs.

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Identification of Potential Feature Genes in CRSwNP Using Bioinformatics Analysis and Machine Learning Strategies

Wang,

Xu,

et al. 2024

JIR

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Purpose The pathogenesis of CRSwNP is complex and not yet fully explored, so we aimed to identify the pivotal hub genes and associated pathways of CRSwNP, to facilitate the detection of novel diagnostic or therapeutic targets. Methods Utilizing two CRSwNP sequencing datasets from GEO, differential expression gene analysis, WGCNA, and three machine learning methods (LASSO, RF and SVM-RFE) were applied to screen for hub genes. A diagnostic model was then formulated utilizing hub genes, and the AUC was generated to evaluate the performance of the prognostic model and candidate genes. Hub genes were validated through the validation set and qPCR performed on normal mice and CRSwNP mouse model. Lastly, the ssGSEA algorithm was employed to assess the differences in immune infiltration levels. Results A total of 239 DEGs were identified, with 170 upregulated and 69 downregulated in CRSwNP. Enrichment analysis revealed that these DEGs were primarily enriched in pathways related to nucleocytoplasmic transport and HIF-1 signaling pathway. Data yielded by WGCNA analysis contained 183 DEGs. The application of three machine learning algorithms identified 11 hub genes. Following concurrent validation analysis with the validation set and qPCR performed after establishing the mouse model confirmed the overexpression of BTBD10, ERAP1, GIPC1, and PEX6 in CRSwNP. The examination of immune cell infiltration suggested that the infiltration rate of type 2 T helper cell and memory B cell experienced a decline in the CRSwNP group. Conversely, the infiltration rates of Immature dendritic cell and Effector memory CD8 T cell were positive correlation. Conclusion This study successfully identified and validated BTBD10, ERAP1, GIPC1, and PEX6 as potential novel diagnostic or therapeutic targets for CRSwNP, which offers a fresh perspective and a theoretical foundation for the diagnostic prediction and therapeutic approach to CRSwNP.

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Structure of the peroxisomal Pex1/Pex6 ATPase complex bound to a substrate

Cited by 3 publications

References 99 publications

The peroxisome: an update on mysteries 3.0

The peroxisome: an update on mysteries 3.0

PEX1^G843Dremains functional in peroxisome biogenesis but is rapidly degraded by the proteasome

Identification of Potential Feature Genes in CRSwNP Using Bioinformatics Analysis and Machine Learning Strategies

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Structure of the peroxisomal Pex1/Pex6 ATPase complex bound to a substrate

Cited by 3 publications

References 99 publications

The peroxisome: an update on mysteries 3.0

The peroxisome: an update on mysteries 3.0

PEX1G843Dremains functional in peroxisome biogenesis but is rapidly degraded by the proteasome

Identification of Potential Feature Genes in CRSwNP Using Bioinformatics Analysis and Machine Learning Strategies

Contact Info

Product

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PEX1^G843Dremains functional in peroxisome biogenesis but is rapidly degraded by the proteasome