Competitive Microtubule Binding of PEX14 Coordinates Peroxisomal Protein Import and Motility

Reuter, Maren; Kooshapur, Hamed; Suda, Jeff-Gordian; Gaussmann, Stefan; Neuhaus, Alexander; Brühl, Lena; Bharti, Pratima; Jung, Martin; Schliebs, Wolfgang; Sattler, Michael; Erdmann, Ralf

doi:10.1016/j.jmb.2020.166765

Cited by 13 publications

(9 citation statements)

References 49 publications

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“…Targeting of the tail-anchored membrane proteins to peroxisomes is mediated by a combination of biochemical properties of the TMD and tail region (TMD hydrophobicity; positive net charge of the tail) and depends on PEX19, the import receptor/chaperone for PMPs ( Costello et al, 2017a ; Figure 2 ). In addition to its role in matrix protein import, PEX14 may act as docking factor to microtubules via its N-terminal tubulin binding domain (aa 1-78) ( Reuter et al, 2021 ), which is conserved between H. sapiens and D. rerio .…”

Section: Resultsmentioning

confidence: 99%

Insights Into the Peroxisomal Protein Inventory of Zebrafish

et al. 2022

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Peroxisomes are ubiquitous, oxidative subcellular organelles with important functions in cellular lipid metabolism and redox homeostasis. Loss of peroxisomal functions causes severe disorders with developmental and neurological abnormalities. Zebrafish are emerging as an attractive vertebrate model to study peroxisomal disorders as well as cellular lipid metabolism. Here, we combined bioinformatics analyses with molecular cell biology and reveal the first comprehensive inventory of Danio rerio peroxisomal proteins, which we systematically compared with those of human peroxisomes. Through bioinformatics analysis of all PTS1-carrying proteins, we demonstrate that D. rerio lacks two well-known mammalian peroxisomal proteins (BAAT and ZADH2/PTGR3), but possesses a putative peroxisomal malate synthase (Mlsl) and verified differences in the presence of purine degrading enzymes. Furthermore, we revealed novel candidate peroxisomal proteins in D. rerio, whose function and localisation is discussed. Our findings confirm the suitability of zebrafish as a vertebrate model for peroxisome research and open possibilities for the study of novel peroxisomal candidate proteins in zebrafish and humans.

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Section: Resultsmentioning

confidence: 99%

Insights Into the Peroxisomal Protein Inventory of Zebrafish

et al. 2022

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“…Similar to PEX13, the orientation of PEX14 is controversial and discussed in the field. Studies found PEX14 NTD to be a docking site for PEX5 15 , 16 and for β-tubulin 45 , 46 , implying that the PEX14 NTD must be facing the cytosol at certain times. In contrast, proteinase K assays with peroxisomes isolated from rat liver or Xenopus eggs locate the N-terminal domain of PEX14 in the peroxisomal matrix 22 , 44 .…”

Section: Discussionmentioning

confidence: 99%

Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif

Gaussmann,

Peschel,

Ott

et al. 2024

Nat Commun

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Import of proteins into peroxisomes depends on PEX5, PEX13 and PEX14. By combining biochemical methods and structural biology, we show that the C-terminal SH3 domain of PEX13 mediates intramolecular interactions with a proximal FxxxF motif. The SH3 domain also binds WxxxF peptide motifs in the import receptor PEX5, demonstrating evolutionary conservation of such interactions from yeast to human. Strikingly, intramolecular interaction of the PEX13 FxxxF motif regulates binding of PEX5 WxxxF/Y motifs to the PEX13 SH3 domain. Crystal structures reveal how FxxxF and WxxxF/Y motifs are recognized by a non-canonical surface on the SH3 domain. The PEX13 FxxxF motif also mediates binding to PEX14. Surprisingly, the potential PxxP binding surface of the SH3 domain does not recognize PEX14 PxxP motifs, distinct from its yeast ortholog. Our data show that the dynamic network of PEX13 interactions with PEX5 and PEX14, mediated by diaromatic peptide motifs, modulates peroxisomal matrix import.

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“…In addition, other peroxins are involved in the division and proliferation of peroxisomes (see 2.4). Some peroxins may execute multiple functions and play a role in pexophagy (PEX3) [3] or in the tethering of peroxisomes to the cytoskeleton (PEX14) [4]. Complete inactivation of peroxins that are required for both peroxisome targeting signal 1 (PTS1) and PTS2 import, so far 12 established in mammals, causes Zellweger syndrome, the most severe peroxisomal disorder in men, usually leading to death within the first year of life [1].…”

Section: Peroxisome Biogenesis: Global Knockout Mice With Combined Pt...mentioning

confidence: 99%

Mouse Models to Study Peroxisomal Functions and Disorders: Overview, Caveats, and Recommendations

Kocherlakota¹,

Swinkels²,

Veldhoven³

et al. 2023

Methods in Molecular Biology

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During the last three decades many mouse lines were created or identified that are deficient in one or more peroxisomal functions. Different methodologies were applied to obtain global, hypomorph, cell type selective, inducible and knockin mice. Whereas some models closely mimic pathologies in patients, others strongly deviate or no human counterpart has been reported. Often, mice, apparently endowed with a stronger transcriptional adaptation, have to be challenged with dietary additions or restrictions in order to trigger phenotypic changes. Depending on the inactivated peroxisomal protein, several approaches can be taken to validate the loss-of-function. Here, an overview is given of the available mouse models and their most important characteristics.

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Competitive Microtubule Binding of PEX14 Coordinates Peroxisomal Protein Import and Motility

Cited by 13 publications

References 49 publications

Insights Into the Peroxisomal Protein Inventory of Zebrafish

Insights Into the Peroxisomal Protein Inventory of Zebrafish

Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif

Mouse Models to Study Peroxisomal Functions and Disorders: Overview, Caveats, and Recommendations

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