Dokument

Zusammenfassung:
Glutaredoxine (Grx’e) als Proteine der Thioredoxin (Trx)-Familie sorgen für ein reduzierendes Milieu in Säugerzellen. Die Familie der Glutaredoxine teilt sich in Monothiol-Grx’e (Grx3 und Grx5) und Dithiol- Grx’e (Grx1 und Grx2) auf, die im Nukleus, im Zytoplasma oder in den Mitochondrien lokalisiert sind. Grx’e sind an einer Vielzahl von biologischen Prozessen, wie beispielsweise der Signaltransduktion, beteiligt. Im Rahmen dieser Arbeit wurde das bisher kaum beschriebene monothiol Glutaredoxin 3 detaillierter untersucht und biochemisch charakterisiert. Darüber hinaus wurden mögliche Funktionen von Grx3 in vivo untersucht. In den Datenbanken fanden sich zwei homologe Grx3-Sequenzen. Eine in silico-Analyse zeigte, dass es sich bei der einen Sequenz um die eines Pseudogens und bei der anderen um das codierende Gen handelte. In einer phylogenetischen Stammbaumanalyse stellte sich heraus, dass Grx3 ein hochkonserviertes Protein war. In Lokalisationsstudien wurde Grx3 als zytosolisches und nukleäres ubiquitär exprimiertes Protein identifiziert. In den letzten Jahren wurde ein Zusammenhang zwischen Grx’en und Fe/S-Zentren beschrieben. In dieser Dissertation wurde erstmals die Koordination eines Fe/S-Zentrums für das humane Grx3 gezeigt. Tatsächlich zeigten biochemische Analysen, dass durch Grx3 2[2Fe-2S]-Zentren in vitro und in vivo koordiniert werden. Ferner zeigte sich, dass zwei Grx3-Moleküle durch die beiden Fe/S-Zentren dimerisierten. Funktionell wurde Grx3 in der Literatur bisher als Protein zum Schutz vor einer Hypertrophie des Herzens beschrieben. Auch wurden Grx3 Funktionen in der Immunzellaktivierung zugeschrieben. Im Rahmen dieser Arbeit wurden Hinweise für weitere Funktionen von Grx3 in der Zelle ermittelt. In der Analyse der differentiellen Genexpression in HeLa-Zellen nach Stimulation mit Phorbolester (PMA) deutete sich ein Einfluss von Grx3 auf zytoskeletale Prozesse an. Eine Untersuchung des Migrationsverhaltens von Grx3 zeigte, dass HeLa-Zellen in Abwesenheit von Grx3 schneller migrierten. Durch seine exklusive Expression in den Germinativen Zentren von Lymphknoten und in der T-Zell-Zone der Milz könnte Grx3 eine Funktion in der inflammatorischen Antwort einnehmen. Der wohl deutlichste Effekt von Grx3 auf der Ebene zellulärer Prozesse konnte in der Verteilung von Eisen in der Zelle beschrieben werden. Eine Reduktion des endogenen Grx3-Levels durch siRNA resultierte in Defekten in der Übertragung von Fe/S-Zentren auf Zielproteine und in einem für Eisenmangel typischen Phänotyp in HeLa-Zellen. Diese Resultate könnten bei der Aufklärung von bisher kaum beschriebenen Prozessen des zellulären Eisenmetabolismus helfen, wie z. B. der Verteilung von Eisen vom „freien“ Eisenpool auf Proteine. Ein zentraler Punkt in diesen zukünftigen Studien würde in der Aufklärung der durch das Fe/S-Zentrum vermittelten Funktionen des Grx3-Dimers liegen.

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