Isoform-specific domain organization determines conformation and function of the peroxisomal biogenesis factor PEX26

• Published in: Biochimica et biophysica acta. Molecular cell research Vol. 1866; no. 3; pp. 518 - 531
• Main Authors: Guder, Philipp, Lotz-Havla, Amelie S., Woidy, Mathias, Reiß, Dunja D., Danecka, Marta K., Schatz, Ulrich A., Becker, Marc, Ensenauer, Regina, Pagel, Philipp, Büttner, Lars, Muntau, Ania C., Gersting, Søren W.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-03-2019
• Subjects: Bioluminescence resonance energy transfer (BRET); Heptad repeat; Oligomerization; Peroxisomal biogenesis; Peroxisomal biogenesis disorders (PBD); Peroxisomal function; PEX26; Zellweger syndrome; Peroxisomal function; Oligomerization; Bioluminescence resonance energy transfer (BRET); Peroxisomal biogenesis; Zellweger syndrome; Heptad repeat; Peroxisomal biogenesis disorders (PBD); PEX26
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2018.10.013

Peroxisomal biogenesis factor PEX26 is a membrane anchor for the multi-subunit PEX1-PEX6 protein complex that controls ubiquitination and dislocation of PEX5 cargo receptors for peroxisomal matrix protein import. PEX26 associates with the peroxisomal translocation pore via PEX14 and a splice variant (PEX26Δex5) of unknown function has been reported. Here, we demonstrate PEX26 homooligomerization mediated by two heptad repeat domains adjacent to the transmembrane domain. We show that isoform-specific domain organization determines PEX26 oligomerization and impacts peroxisomal β-oxidation and proliferation. PEX26 and PEX26Δex5 displayed different patterns of interaction with PEX2-PEX10 or PEX13-PEX14 complexes, which relate to distinct pre-peroxisomes in the de novo synthesis pathway. Our data support an alternative PEX14-dependent mechanism of peroxisomal membrane association for the splice variant, which lacks a transmembrane domain. Structure-function relationships of PEX26 isoforms explain an extended function in peroxisomal homeostasis and these findings may improve our understanding of the broad phenotype of PEX26-associated human disorders.
•C-tail membrane anchored PEX26 recruits PEX1-PEX6 complexes to peroxisomes.•Peroxisomal PEX26 homooligomerization is mediated by two heptad repeat domains.•Isoform-specific domain organization determines PEX26 oligomerization and impacts peroxisomal β-oxidation and proliferation.•A splice variant, lacking a transmembrane domain, associates with peroxisomes by an alternative PEX14-dependent mechanism.