Summary:
Eisen-Schwefel (Fe/S) Cluster gehören zu den ältesten Co-Faktoren und sind unabdingbar für die Funktion vieler Proteine. Die Synthese von Fe/S Clustern und deren Insertion in Apoproteine sind komplexe biochemische Vorgänge. In Mitochondrien wird die Biogenese von Fe/S Proteinen durch die ISC Assemblierungsmaschinerie (Iron-Sulfur Cluster Assembly) in drei Stufen durchgeführt. Im ersten Schritt wird ein Fe/S Cluster de novo aus Eisenionen und Sulfid, das durch eine Cysteindesulfurase bereitgestellt wird, auf dem Gerüstprotein Isu1 assembliert. In einem zweiten Schritt wird der Isu1-gebundene Fe/S Cluster mittels eines spezifischen Chaperonsystems dissoziiert, um dann schließlich durch spezielle Reifungsfaktoren auf die verschiedenen Zielproteine übertragen zu werden. Obwohl bereits einige Faktoren identifiziert wurden, die am Transfer von Fe/S Clustern auf Zielproteine beteiligt sind, ist über deren Zusammenspiel und ihre jeweilige spezifische Funktion wenig bekannt. Diese Arbeit konzentriert sich auf die Rolle des Monothiol Glutaredoxin Grx5, der BolA-ähnlichen Proteine Aim1 und Yal044W sowie des Nfu1 in den späten Phasen der Fe/S Proteinbiogenese.
Mutationen im humanen GLRX5 wurden mit mikrozytischer Anämie in Verbindung gebracht und eine Deletion im Zebrafisch ist embryonisch letal. In der Hefe S. cerevisiae ist Grx5 nicht essentiell, jedoch zeigen Zellen ohne Grx5 niedrige Enzymaktivitäten von Fe/S Proteinen, eine Akkumulation von mitochondrialem Eisen und oxidativen Stress. Es wurde bereits gezeigt, dass die Depletion von Grx5 eine Akkumulation von Fe/S Clustern auf Isu1 hervorruft, und diese nicht auf Zielproteine übertragen werden können. In dieser Arbeit konnte gezeigt werden, dass Grx5 einen Fe/S Cluster in vivo bindet, der für die Reifung aller zellulärer Fe/S Proteine benötigt wird, unabhängig vom Typ des gebundenen Fe/S Co-Faktors und deren subzellulärer Lokalisation. Grx5 und Isu1 interagieren gleichzeitig mit dem Hsp70 Chaperon Ssq1 an unterschiedlichen Bindungsstellen. Grx5 stimuliert dabei nicht die ATPase Aktivität von Ssq1 und bindet bevorzugt an die ADP-Form von Ssq1. Die räumliche Nähe von Isu1 und Grx5 am Chaperon erleichtert den schnellen Fe/S Cluster Transfer von Isu1 auf Grx5. Somit verbindet Grx5 den Prozess der de novo Fe/S Clusterbiosynthese auf Isu1 mit dem Transfer des fertigen Fe/S Clusters auf entsprechende Zielproteine.
BolA-ähnliche Proteine sind mit den Monothiol Glutaredoxinen über bioinformatische und experimentelle Ansätze in Zusammenhang gebracht worden. Um die Funktion der mitochondrialen BolA-ähnlichen Proteine zu studieren, wurden Hefezellen untersucht, in denen die Gene für Aim1 und Yal044W deletiert wurden. Während die Rolle der Yal044W in der Fe/S Proteinbiogenese unklar blieb, zeigten aim1Δ Zellen eine 50%-ige Abnahme der Enzym-Aktivitäten der Succinatdehydrogenase und der Lipoat-abhängigen Enzyme Pyruvat- und α-Ketoglutarat-Dehydrogenase. Die Aktivitäten der letzteren Enzyme sind abhängig von der Lipoat-Synthase Lip5, einem Fe/S Protein. Aim1 scheint für die katalytische Aktivierung, aber nicht für die de novo Insertion von Fe/S Clustern in Lip5 benötigt zu werden. Der Phänotyp von aim1Δ Zellen in Hefe ist kompatibel mit dem humaner Zellen aus Patienten mit fataler infantiler Enzephalopathie und/oder pulmonaler Hypertonie. Diese Erkrankung wird u.a. durch Mutationen im humanen Aim1 Homolog BOLA3 verursacht. Offensichtlich ist die Rolle der Aim1 Proteine als spezialisierte ISC Überträger-Proteine, die bei der Reifung einer Unterklasse mitochondrialer [4Fe-4S]-Proteine benötigt werden, in Eukaryoten konserviert.
Mutationen im humanen NFU1 wurden ebenfalls mit fataler infantiler Enzephalopathie und/ oder pulmonaler Hypertonie in Verbindung gebracht. NFU1 wird für die Reifung der Fe/S Cluster der Atmungskettenkomplexe I und II und der Lipoat-Synthase in humanen Zellen benötigt. Nfu1-ähnliche Proteine binden Fe/S Cluster in vitro, woraus geschlossen wurde, dass Nfu1 ein Gerüstprotein ist, dass parallel zu Isu1 arbeitet. In dieser Arbeit wurde gezeigt, dass die Deletion von NFU1 in Hefe eine bis zu 5-fache Abnahme der Aktivitäten der Succinat-dehydrogenase und Lipoat-abhängiger Enzyme hervorruft. Dies stimmt mit den Befunden an NFU1 Patientenzellen überein. Hefe Nfu1, das eine Patienten-analoge Mutation trägt (Gly194Cys), bindet einen Fe/S Cluster wesentlich stabiler als das Wildtyp-Protein, und erlaubte somit erstmals den Nachweis einer Fe/S Cluster Bindung auf Nfu1 in vivo. Die Fe/S Cluster Bindung auf Nfu1 war abhängig von der ISC Assemblierungsmaschinerie einschließlich Isu1, was ausschließt, dass Nfu1 ein zu Isu1 alternatives Gerüstprotein ist. Aufgrund der verminderten Labilität des gebundenen Fe/S Clusters in Nfu1-Gly194Cys konnte dieses die Defekte der nfu1∆-Zellen in Hefe nur unvollständig retten, womit ein Einblick in die Krankheitsentstehung in menschlichen Patienten gegeben wurde.
Die vorliegende Arbeit trägt zu einem besseren Verständnis bei, wie Fe/S Cluster nach ihrer de novo Synthese auf dem Gerüstprotein Isu1 in den Mitochondrien weiter transferiert werden. Die hier gezeigte gleichzeitige Interaktion von Isu1 und Grx5 auf dem spezialisierten Hsp70 Chaperon Ssq1 ermöglicht einen effizienten Transfer der Fe/S Cluster von Isu1 zu Grx5, das wiederum als wichtiger ISC Faktor für die Reifung aller zellulärer Fe/S Proteine charakterisiert werden konnte. Weiterhin konnte eine unterstützende Funktion der Hefeproteine Nfu1 und Aim1 als spezialisierte Reifungsfaktoren nachgewiesen werden. Diese Erkenntnisse erlauben einen besseren Einblick in das mechanistische Zusammenspiel der späten Komponenten der mitochondrialen ISC Assemblierungsmaschinerie.
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