Life sciences Biowissenschaften, Biologie 2011 Webert, Holger Webert Holger Chemie https://archiv.ub.uni-marburg.de/diss/z2011/0102/cover.png ISC-Maschinerie cofactor-biogenesis doctoralThesis monograph Structural and functional characterization of components of the eukaryotic iron-sulfur-cluster biogenesis machinery 2011-06-28 Kofaktor-Biogenese opus:3720 ISC-machinery Fachbereich Chemie Iron-sulfur-cluster 2011-08-08 ths Prof. Dr. Lill Roland Lill, Roland (Prof. Dr.) Philipps-Universität Marburg Publikationsserver der Universitätsbibliothek Marburg Universitätsbibliothek Marburg Biogenese iron-sulfur-protein application/pdf Eisen-Schwefel-Protein, Ferredoxin Strukturelle und funktionelle Charakterisierung von Komponenten der eukaryotischen Eisen-Schwefel-Cluster-Biogenese-Maschinerie ferredoxin https://doi.org/10.17192/z2011.0102 Eisen-Schwefel-Cluster (Fe/S-Cluster) sind essentielle und vielseitige Kofaktoren zahlreicher Proteine und kommen in allen bekannten Lebensformen vor. Trotz ihrer vergleichsweise einfachen Struktur erfordert ihre Biosynthese und der Einbau in Apoproteine komplexe Synthesemaschinerien, die evolutionär konserviert sind. Im eukaryotischen Modellorganismus S. cerevisiae hängt die Biogenese mitochondrialer Fe/S-Proteine von der mitochondrialen ISC-Maschinerie ab, während die Synthese zytosolischer und nukleärer Fe/S-Proteine zusätzlich noch die mitochondriale ISC-Export- und die zytosolische CIA Maschinerie erfordert. Sowohl die Biosynthese mitochondrialer Fe/S-Proteine als auch die von zytosolischen oder nukleären Fe/S Proteinen kann in zwei biochemische Hauptreaktionen eingeteilt werden. Nach der de novo Assemblierung eines Fe/S Clusters auf einem Gerüstprotein wird der so vorgefertigte Cluster auf das eigentliche Zielprotein übertragen und dort inseriert. Während nahezu alle Komponenten der Biogenesemaschinerien mittlerweile bekannt sind, ist der molekulare Mechanismus der in vivo Fe/S-Cluster Biosynthese noch in vielen Punkten ungeklärt. Für die de novo Assemblierung von Fe/S-Clustern auf dem Gerüstprotein Isu1 der mitochondrialen ISC-Maschinerie ist die Elektronenübertragung durch ein Ferredoxin essentiell. Im ersten Teil dieser Arbeit wurde gezeigt, dass sich eukaryotische mitochondriale Ferredoxine funktionell und strukturell in drei Untergruppen aufteilen lassen. Während die Mitglieder der ersten Untergruppe wie humanes Ferredoxin Fdx2 spezifisch an der Fe/S-Cluster Biogenese und der Häm A Biosynthese beteiligt sind, liefern die Ferredoxine der zweiten Untergruppe wie das Fdx2-verwandte humane Ferredoxin Fdx1 Elektronen für die Steroidbiogenese durch Cytochrom P450 Enzyme (CYP). Die dritte Untergruppe bilden die noch vielseitigeren Ferredoxine aus Pilzen wie Yah1 aus S. cerevisiae, das neben den Funktionen des Fdx2 auch noch eine essentielle Rolle in der Biosynthese von Koenzym Q6 spielt. In dieser Arbeit wurde die Struktur des humanen Ferredoxins Fdx2 mit einer Auflösung von 1,7 Å durch Röntgenstrukturanalyse bestimmt. Im Vergleich zur schon bekannten Struktur von Fdx1 besitzt Fdx2 eine nahezu identische Faltung. Strukturelle Unterschiede wurden nur in der α-Helix C sowie im Bereich nach α-Helix C gefunden. Dies warf die Frage nach der strukturellen Basis für die hohe Substratspezifität der beiden humanen Ferredoxine auf. Durch genetische und biochemische Experimente konnte gezeigt werden, dass der hoch konservierte C Terminus von Fdx2 essentiell für die in vivo Funktion des Proteins in der Biogenese von Fe/S-Clustern ist. Ein in der Fe/S-Cluster Biogenese funktionelles Fdx1 konnte durch die Übertragung der 27 C-terminalen Aminosäuren des Fdx2 an den Fdx1 C-Terminus erzeugt werden. Weitere Sequenzaustausche im Bereich der α Helix C sowie in der Fe/S-Cluster-bedeckenden Schlaufe erhöhten die Funktionsfähigkeit des Fdx1 in der Fe/S Proteinbiogenese, was die Rolle dieser Reste bei der Erzeugung der Substratspezifität nachweist. Umgekehrt gelang es, in Fdx2 eine Elektronenübertragungsfunktion auf CYP einzuführen. Die hierfür kritische Mutation wurde als R73E identifiziert. Die Umfunktionalisierung des Fdx2 war überraschenderweise nicht abhängig von der Sequenz am C Terminus. Da die Funktionsübertragung durch die R73E Mutation nur partiell erfolgte, scheint diese Schlüsselaminosäure nicht allein verantwortlich für die Spezifität von Fdx1 für CYP zu sein. Der positiv geladene Rest R73 im Fdx2 könnte daher eher verhindern, dass dieses Ferredoxin Elektronen auf CYP übertragen kann. Die theoretische Analyse des Dipolmomentes der Ferredoxine Fdx1 und Fdx2 ergab, dass die Dipolmomentvektoren der beiden Ferredoxine nahezu senkrecht zueinander stehen. Da die Interaktion der hochgeladenen Ferredoxine mit ihren Proteinpartnern auf Ladungswechselwirkungen beruht, deutet dieser Unterschied auf einen elektrostatischen Steuerungseffekt bei der Annäherung der Ferredoxine an den entsprechenden Elektronenakzeptor als mögliche Unterstützung der Funktionsspezifität hin. Ein solcher Steuerungseffekt könnte ein allgemeines Prinzip bei der Annäherung von Proteinen in transienten Elektronentransferkomplexen darstellen. .. urn:nbn:de:hebis:04-z2011-01023 German 2011-05-12 Iron-sulfur clusters (Fe/S-clusters) are essential and versatile cofactors of numerous proteins and are present in virtually all living organism. Despite their relatively simple structure, their biosynthesis and assembly into apoproteins requires complex multi-protein biosynthesis-machineries which are conserved in eukaryotes. In the eukaryotic model organism S. cerevisiae the biogenesis of mitochondrial Fe/S-proteins depends on the mitochondrial ISC assembly system, whereas the synthesis of cytosolic and nuclear Fe/S-proteins additionally requires the mitochondrial ISC export machinery and the cytosolic CIA machinery. The biosynthesis of both mitochondrial and cytosolic nuclear Fe/S-proteins occurs in two major steps. First, an Fe/S-cluster is synthesized de novo on a scaffold protein. Second, the preassembled Fe/S-cluster is transferred and inserted in the target apoprotein. Whereas nearly all components of the biosynthesis machineries have been identified, the molecular mechanisms of Fe/S-cluster biosynthesis within the living cell are widely unknown. The de novo synthesis of Fe/S-clusters on the scaffold protein Isu1 of the mitochondrial ISC-assembly machinery requires an electron transfer by the NAD(P)H - ferredoxin reductase - ferredoxin chain. In the first part of this study it was shown that mitochondrial ferredoxins functionally and structurally are comprised of three distinct subclasses. Whereas members of the first subclass like human ferredoxin Fdx2 are specifically required for Fe/S-cluster biogenesis and heme A biosynthesis, ferredoxins of the second subclass such as the Fdx2-related human Fdx1 deliver electrons for steroid biosynthesis by cytochrome P450 enzymes (CYP). The third subclass is formed by the even more versatile ferredoxins from fungi including Yah1 from S. cerevisiae, which in addition to the functions of Fdx2, also plays an important role in the biosynthesis of coenzyme Q6. In this work, the three dimensional structure of human ferredoxin Fdx2 was determined at 1,7 Å resolution using X ray structure analysis. The folding of Fdx2 is virtually identical to that of Fdx1, despite the distinct substrate specificities of the two proteins. Structural differences were only observed in α-helix C and the region right after α-helix C. Genetic and biochemical experiments showed that the highly conserved C-terminus of Fdx2 is essential for its specific in vivo function in the biogenesis of Fe/S-clusters. An Fdx1 protein, which functions in Fe/S-cluster biogenesis, was successfully generated after exchange of the last 27 amino acids against the respective sequence from Fdx2. Further amino acid exchanges in the region of α-helix C and the loop covering the Fe/S-cluster increased the functionality showing the importance of these regions for substrate specificity. Vice versa, the generation of electron transfer capacity from Fdx2 to CYP was successful after introduction of the key mutation R73E. In this case, the gain of function was independent of the C terminus. The efficiency of specificity transfer was not complete; hence the key residue 73 is not solely responsible for the functional specificity. In fact, other global factors within the structure of the protein contribute to the specificity. It appears that the positively charged residue R73 in Fdx2 may inhibit transfer of electrons to CYP. Theoretical analysis of the dipole moment revealed an almost perpendicular orientation within the ferredoxins Fdx1 and Fdx2, despite their striking structural similarity. 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