Zusammenfassung:
In S. cerevisiae sind drei Proteinmaschinerien für die de novo Biogenese von Fe/S-Clustern und deren Inkorporation in Zielproteine verantwortlich: die mitochondriale ISC- (iron sulfur cluster) Assemblierungsmaschinerie, das ISC-Export-System sowie das CIA- (cytosolic iron-sulfur-protein assembly) System. Der Mechanismus der de novo Biogenese eines [2Fe-2S]-Clusters durch die Komponenten der Kern-ISC-Maschinerie ist bereits gut untersucht. Wenig ist hingegen über den Prozess der [2Fe-2S]- nach [4Fe-4S]-Cluster-Konversion bekannt, der durch die späten ISC-Komponenten katalysiert wird sowie über die Mechanismen, mit denen Fe/S-Zielproteine an die ISC-Maschinerie rekrutiert werden. Die vorliegende Dissertation beschäftigt sich mit diesen zwei Teilaspekten aus dem letzten Schritt der Fe/S-Cluster-Biogenese. Im ersten Teilprojekt dieser Arbeit wurde analysiert, in welcher Form Apo-Fe/S-Proteine an die ISC-Maschinerie herangeführt werden. Hierbei stand die Frage im Vordergrund, ob und wie die Zelle die freien Thiolgruppen von Fe/S-Cluster ligierenden Cysteinen in der Apo-Form vor oxidativen Modifikationen schützt. Mittels massenspektrometrischer Analyse wurde gezeigt, dass mitochondriale Fe/S-Proteine in Zellen mit Defekten in der ISC-Maschinerie mit mehreren Massenaddukten von +30 bis +32 Da modifiziert werden. Bei diesen Modifikationen handelt es sich wahrscheinlich um Schwefeladditionen an die Cysteinliganden der Apo-Fe/S-Proteine in Form von verbrückenden Polysulfiden. Diese Modifikationen treten ebenfalls in geringem Maße unter normalen Wachstumsbedingungen in Wildtypzellen auf und werden verstärkt unter Eisenmangelbedingungen beobachtet. Da die Cysteinaddukte reduktiv entfernt werden können, liegt der Schluss nahe, dass es sich bei der Modifikation der Cysteinliganden von Apo-Fe/S-Proteinen mit Per- oder Polysulfiden um einen physiologischen Schutzmechanismus vor oxidationsbedingter Degradation handelt.
Im zweiten Teilprojekt wurde ein neues System zur systematischen Analyse von Protein-Protein-Interaktionen in Mitochondrien von S. cerevisiae entwickelt um Interaktionen der späten ISC-Komponenten Isa1, Isa2 und Iba57 zu charakterisieren. Die Daten dieses Renilla Split-Luciferase-Testsystems legen den Schluss nahe, dass Isa1, Isa2 und Iba57 einen trimeren Komplex ausbilden, dessen Assemblierung in vivo von einer funktionierenden ISC-Maschinerie abhängig ist. Isa1 und Isa2 interagieren weiterhin mit dem Monothiol Glutaredoxin Grx5, welches den in der frühen ISC-Maschinerie synthetisierten [2Fe-2S]-Cluster von dem Gerüstprotein Isu1 übernimmt und an [2Fe 2S]-Zielproteine weiterreicht. Die Interaktion mit Isa1 und Isa2 spricht dafür, dass Grx5 seinen [2Fe-2S]-Cluster ebenfalls an die späte ISC-Maschinerie zur Konversion in einen [4Fe-4S]-Cluster weiterreichen könnte. Zudem interagierte das mitochondriale Ferredoxin Yah1 mit den späten ISC-Komponenten. Dies könnte bedeuten, dass Yah1 Elektronen für einen reduktiven Reaktionsschritt während der Fe/S-Cluster-Konversion bereitstellt. Da das Renilla Split-Luciferase-Testsystem zu einer konzentrationsabhängigen Assemblierung der Teildomänen in Mitochondrien tendiert, sollten die hier beobachteten Interaktionen mit einer weiteren Methode verifiziert werden.
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