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Functional Characterization of the Human Peroxins PEX3 and PEX19, Proteins Essential for Early Peroxisomal Membrane Biogenesis

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Functional Characterization of the Human Peroxins PEX3 and PEX19, Proteins Essential for Early Peroxisomal Membrane Biogenesis Institut für Experimentelle Genetik, GSF-Forschungszentrum für Umwelt und Gesundheit, Neuherberg Dr. von Haunersches Kinderspital Functional Characterization of the Human Peroxins PEX3 and PEX19, Proteins Essential for Early Peroxisomal Membrane Biogenesis Peter Uli Mayerhofer Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr.rer.nat. Alfons Gierl Prüfer der Dissertation: 1. Priv.-Doz. Dr.rer.nat. Dr.rer.biol.hum.habil. Jerzy Adamski 2. Univ.-Prof. Dr.rer.nat. Hans-Werner Mewes 3. Univ.-Prof. Dr.med. Adelbert A. Roscher, Ludwig-Maximilians-Universität München Die Dissertation wurde am 11.07.2002 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 01.03.2003 angenommen. TABLE OF CONTENTS i Table of Contents Abstract ................................................................................................................................iii Zusammenfassung .................................................................................................................v CHAPTER I: Introduction ..................................................................................................... 1 1 Peroxisomes: Morphology and Metabolic Functions ................................................... 2 2 Peroxisomal Diseases.................................................................................................. 5 2.1 X-Linked Adrenoleukodystrophy: A Peroxisomal Single Enzyme deficiency......... 6 2.2 Peroxisomal Biogenesis Disorders............................................................................ 8 3 The Peroxisomal Biogenesis ..................................................................................... 10 3.1 Targeting and Import of Matrix Enzymes ............................................................... 13 3.2 Peroxisomal Membrane Biogenesis........................................................................ 17 3.3 PEX3 and PEX19, Peroxins Expected to be Involved in the Early Steps of Peroxisomal Biogenesis ......................................................................................... 20 CHAPTER II: Aims of the Thesis....................................................................................... 22 CHAPTER III: Results and Discussion ................................................................................ 24 1 PEX19 Interacts With a Variety of Peroxisomal Membrane Proteins......................... 25 2 Characterization of PEX19 Splice Variants: Functional Diversity and New Insights in the Role of Posttranslational Farnesylation ............................. 27 3 Proposed Biological Functions of PEX19.................................................................. 30 4 PEX3, a Key Factor in Early Human Peroxisome Synthesis ...................................... 32 5 Two-Path Model for Peroxisome Membrane Synthesis in Mammalian Cells ............. 35 6 Further Perspectives: Identification of the Origin of the Endomembrane Template.... 37 References........................................................................................................................... 38 Appendix 1: Full Length cDNA Cloning, Promoter Sequence, and Genomic Organization of the Human Adrenoleukodystrophy Related (ALDR) Gene Functionally Redundant to the Gene Responsible for X-Linked Adrenoleukodystrophy....... 50 Appendix 2: Human Adrenoleukodystrophy Protein and Related Peroxisomal ABC Transporters Interact with the Peroxisomal Assembly Protein PEX19p ........... 63 Appendix 3: Two Splice Variants of Human PEX19 Exhibit Distinct Functions in Peroxisomal Assembly ................................................................................ 77 Appendix 4: Genomic Organization, Expression Analysis, and Chromosomal Localization of the Mouse PEX3 Gene Encoding a Peroxisomal Assembly Protein ............. 90 TABLE OF CONTENTS ii Appendix 5: The Human PEX3 Gene Encoding a Peroxisomal Assembly Protein: Genomic Organization, Positional Mapping, and Mutation Analysis in Candidate Phenotypes ............................................................................... 100 Appendix 6: Defective Peroxisome Membrane Synthesis Due to Mutations in Human PEX3 Causes Zellweger Syndrome, Complementation Group G ... 112 Abbreviations .................................................................................................................... 125 Danksagung....................................................................................................................... 126 List of Publications............................................................................................................ 127 Curriculum Vitae ............................................................................................................... 130 ABSTRACT iii Abstract ABSTRACT iv Abstract Peroxisomes are single-membrane-bound organelles present in virtually all eukaryotic cells. Their significance in human metabolism is illustrated by the existence of severe inherited diseases caused by the failure of peroxisomal biogenesis (peroxisomal biogenesis disorders; PBDs). Proteins required for peroxisomal assembly are termed “peroxins” and are encoded by at least 23 PEX-genes. In most cases, defects in PEX genes lead to a disruption of peroxisomal matrix protein import, whereas various peroxisomal membrane components are synthesized and accumulate in peroxisomal membrane remnants (“peroxisomal ghosts”). Since yeast mutants in PEX3 and PEX19 have been shown to lack peroxisomal ghosts, these peroxins were expected to be involved in the early stages of peroxisomal membrane synthesis. This work focused on the functional characterization of human PEX3 and PEX19 to gain insights into their role in human biology and disease. PEX19 was shown to interact with three peroxisomal ABC half-transporters (Adrenoleukodystrophy protein ALDP, Adrenoleukodystrophy-related protein ALDRP, and the 70 kDa peroxisomal membrane protein PMP70), confirming its role as a broad specific peroxisomal membrane-protein binding-protein. As a prerequisite for these protein-protein interaction assays, the human ALDR gene was characterized. Proteins encoded by two PEX19 splice variants showed a considerable functional diversity as to peroxisomal membrane protein binding and with respect to induction of peroxisomal formation in PEX19-deficient human fibroblasts. Farnesylation of PEX19 was shown not to be essential for these functions. These data provide the first experimental evidence for specific biological functions of the different predicted domains of the PEX19 protein. In order to investigate the molecular details of peroxisomal assembly and to evaluate experimental treatment strategies for the peroxisomal biogenesis disorders, data useful for the future generation of a mouse model with targeted disruption of the PEX3 gene were presented. The human PEX3 gene was characterized with the goal to identify a yet unknown human PEX3-deficient phenotype. Two inactivating PEX3 mutations were detected in two PBDs-patients exhibiting a severe and lethal Zellweger syndrome phenotype. They showed a total lack of morphologically recognizable peroxisomal membrane remnants in their fibroblasts. Expression of the wild type PEX3 cDNA in the mutant cell lines restored peroxisomal biogenesis, establishing PEX3 as a key factor in early human peroxisome synthesis. Taken together, the combined data presented here provide evidence for the essential role of PEX3 and PEX19 in the initial steps of an alternative human peroxisome- formation pathway. In contrast to the theory that peroxisomes can arise exclusively by growth and division of preexisting peroxisomes, this alternative pathway does not require morphologically recognizable peroxisomal membranes. ZUSAMMENFASSUNG v Zusammenfassung ZUSAMMENFASSUNG vi Zusammenfassung Peroxisomen sind von einer einschichtigen Membran umgebene Zellorganellen, die nahezu in allen eukaryontischen Zellen vorkommen. Ihre Bedeutung im menschlichen Stoffwechsel wird durch eine Reihe schwerer genetischer Erkrankungen belegt, die durch Defekte der peroxisomalen Biogenese ausgelöst werden (Peroxisomale Biogenesedefekte, PBD). An der peroxisomalen Biogenese sind mindestens 23 Proteine (Peroxine) beteiligt, die durch PEX- Gene kodiert werden. Meistens wirkt sich der Defekt eines PEX-Gens in einem gestörten peroxisomalen Matrixprotein-Import aus, während peroxisomale Membrankomponenten normal synthetisiert werden und sich in leeren, residualen peroxisomalen Membranstrukturen („peroxisomal ghosts“) ansammeln. Für PEX3-und PEX19-Hefemutanten konnte das Fehlen dieser „peroxisomal ghosts“ gezeigt werden. Diese Beobachtung führten zu der Hypothese, dass beide Peroxine an der frühen peroxisomalen Membransynthese beteiligt sind. Das Ziel dieser Arbeit lag in der funktionellen Charakterisierung der humanen Peroxine PEX3 und PEX19, um neue Erkenntnisse über deren Bedeutung in der Humanbiologie und deren Beteiligung an genetischen Erkrankungen zu erlangen. Es konnte gezeigt werden, dass PEX19 mit drei peroxisomalen ABC-Halb-Transportern (Adrenoleukodystrophieprotein, ALDP; Adrenoleukodystrophie-related Protein, ALDRP; 70 kDa peroxisomalen Membranprotein, PMP70) interagiert. Somit wurde die Rolle von PEX19 als allgemeinspezifisches
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