Publikationsserver der Universitätsbibliothek Marburg
Titel:Rolle der cytosolischen Glutaredoxine im zellulären Eisenmetabolismus in Eukaryoten
Autor:Hoffmann, Bastian
Weitere Beteiligte: Lill, Roland (Prof. Dr.)
Veröffentlicht:2013
URI:https://archiv.ub.uni-marburg.de/diss/z2013/0475
URN: urn:nbn:de:hebis:04-z2013-04757
DOI: https://doi.org/10.17192/z2013.0475
DDC: Biowissenschaften, Biologie
Titel (trans.):Role of the cytosolic monothiol glutaredoxins in iron metabolism of eukaryotes
Publikationsdatum:2013-10-08
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Ironmetabolism, Metabolismus, Ironhomöostasis, Eisenhomöostase, Eisen, Monothiol Glutaredoxine, Saccharomyces cerevisiaem, monothiol glutaredoxins. Saccharomyces cerevisiae, Eisenmetabolismus, Stoffwechsel

Zusammenfassung:
Glutaredoxine kommen in allen phylogenetischen Reichen der Lebewesen vor. Zu dieser Proteinfamilie gehören Dithiol-Glutaredoxine, die ein CPYC Motiv im aktiven Zentrum aufweisen und eine wichtige Rolle bei der Aufrechterhaltung des zellulären Redoxpotentials spielen. Einzeldomänen Monothiol-Glutaredoxine mit einem CGFS Motiv im aktiven Zentrum spielen eine zentrale Funktion bei der Maturierung zellulärer Eisen-Schwefel (Fe/S) Proteine und sind üblicherweise in den Mitochondrien und Chloroplasten lokalisiert. Multidomänen Monothiol-Glutaredoxine sind Fusionsproteine, die aus einer N-terminalen Thioredoxindomäne und einer oder mehreren C-terminalen Monothiol Glutaredoxindomäne(n) bestehen. Diese Unterfamilie der Glutaredoxine kommt im Cytosol und Nukleus fast aller Eukaryoten vor. In der Bäckerhefe S. cerevisiae binden die Multidomänen-Glutaredoxine Grx3 und Grx4 einen Fe/S-Kofaktor und spielen eine essenzielle Rolle bei der Maturierung aller Klassen Eisen-haltiger Proteine und der Regulation der zellulären Eisenhomöostase. Zentrales Ziel der Arbeit war die bessere funktionelle Charakterisierung der Multidomänen Monothiol-Glutaredoxine. Zwei zentrale Fragen standen hierbei im Vordergrund: (1) Welche strukturellen Unterschiede befähigen die ansonsten sehr ähnlichen Glutaredoxine dazu, jeweils spezifische Funktionen zu übernehmen? (2) In wie weit ist die für S. cerevisiae beschriebene Funktion der Multidomänen Glutaredoxine im Eisenmetabolismus höherer Eukaryoten konserviert? Der ersten Frage wurde durch Untersuchungen der Auswirkungen gezielter Mutationen auf die Funktionalität von Grx4 in S. cerevisiae nachgegangen. Diese Analyse zeigte, dass ein Dithiol-Motiv anstelle des Monothiol Motivs im aktiven Zentrum von Grx4 zu einer stark reduzierten Fe/S Clusterbindung und einem moderaten Funktionsverlust dieses Proteins in vivo führt. Hingegen ist ein Prolin im aktiven Zentrum von Grx4 im Gegensatz zu den Einzeldomänen Glutaredoxinen vollkommen kompatibel mit der Bindung eines Fe/S Clusters. Darüber hinaus ist die Thioredoxindomäne von Grx4 absolut essenziell für die Funktion. Wahrscheinlich fungiert diese Domäne als Bindestelle für andere Proteine. Grx3 und Grx4 interagieren direkt mit dem Eisen-regulierten Transkriptionsfaktor Aft1 und inaktivieren Aft1 bei ausreichend verfügbarem Eisen. Es konnte gezeigt werden, dass die Regulation von Aft1 inkompatibel mit einem Dithiol-Motiv im aktiven Zentrum von Grx4 ist und dass Aft1 mit dem C Terminus von Grx4 interagiert. Diese Interaktion ist nicht Eisen-abhängig und ist erhöht, wenn Grx4 keinen Fe/S Cluster gebunden hat. Somit ist nur die Inaktivierung von Aft1 direkt vom Fe/S Cluster von Grx4 abhängig. Insgesamt zeigte diese Arbeit wichtige strukturelle Voraussetzungen für die Funktion der Multidomänen Glutaredoxine im Eisenmetabolismus von S. cerevisiae auf. Zur Beantwortung der zweiten Frage wurden die Auswirkungen der siRNA-vermittelten Depletion von Grx3 in HeLa Zellen untersucht. Grx3-depletierte HeLa Zellen zeigten vergleichbar mit Hefe-Zellen Defekte in der Assemblierung von Fe/S Proteinen des Cytosols und des Zellkerns. Ein Defekt in der Reifung des „Iron Regulatory Protein 1“ (IRP1) führte zum Abbau der Apo-Form dieses Proteins und entsprechenden Auswirkungen auf den Eisenmetabolismus. Im Gegensatz zu Hefe-Zellen zeigten Grx3-depletierte HeLa Zellen keinen Effekt auf die Maturierung mitochondrialer Fe/S Cluster- oder Häm-haltiger Proteine. Trotz des geänderten Eisenmetabolismus wies das Transkriptom von Grx3-depletierten HeLa Zellen keine geänderte Regulation typischer Eisen-regulierter Gene auf. Dazu gehören z.B. Gene, die eine Funktion in den Mitochondrien sowie unter hypoxischen Bedingungen ausüben. Dies und die fehlenden Effekte auf die mitochondrialen Eisen-abhängigen Proteine sind auffällige Unterschiede zu der Hefe. Zusammenfassend konnte eine in allen Eukaryoten konservierte Funktion von Grx3 hinsichtlich der Biogenese von cytosolischen, nicht aber mitochondrialen Fe/S Proteinen nachgewiesen werden.

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