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

Biochim Biophys Acta Mol Cell Res. 2019 Mar;1866(3):518-531. Epub 2018 Oct 23

Philipp Guder ¹ , Amelie S Lotz-Havla ² , Mathias Woidy ¹ , Dunja D Reiß ² , Marta K Danecka ³ ,

Philipp Guder ¹ , Amelie S Lotz-Havla ² , Mathias Woidy ¹ , Dunja D Reiß ² , Marta K Danecka ³ , Ulrich A Schatz ⁴ , Marc Becker ⁵ , Regina Ensenauer ⁶ , Philipp Pagel ⁷ , Lars Büttner ² , Ania C Muntau ⁸ , Søren W Gersting ⁹

+ et al

Author information

¹ University Children's Research@Kinder-UKE, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
² Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany.
³ University Children's Research@Kinder-UKE, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁴ Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria.
⁵ Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany; Labor Becker Olgemöller und Kollegen, 81671 Munich, Germany.
⁶ Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany; Experimental Pediatrics, Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
⁷ Lehrstuhl für Genomorientierte Bioinformatik, Technische Universität, 85350 Freising, Germany; numares GmbH, Josef-Engert-Str. 9, 93053 Regensburg, Germany.
⁸ Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁹ University Children's Research@Kinder-UKE, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: gersting@uke.de.

摘要

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 (PEX26Îex5) 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 Î²-oxidation and proliferation. PEX26 and PEX26Îex5 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.

KEYWORDS: Bioluminescence resonance energy transfer (BRET), Heptad repeat, Oligomerization, PEX26, Peroxisomal biogenesis, Peroxisomal biogenesis disorders (PBD), Peroxisomal function, Zellweger syndrome

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