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Foamy Virus Enzymes Activity, Regulation and Resistance

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Foamy Virus Enzymes Activity, Regulation and Resistance Foamy Virus Enzymes Activity, Regulation and Resistance Dissertation zur Erlangung des Doktorgrades der Fakultät für Biologie, Chemie und Geowissenschaften an der Universität Bayreuth Vorgelegt von Diplom-Biochemiker Maximilian Johannes Hartl Bayreuth, 2009 Die vorliegende Arbeit wurde von August 2006 bis Oktober 2009 am Lehrstuhl für Struktur und Chemie der Biopolymere unter der Leitung von Prof. Dr. Birgitta Wöhrl angefertigt. Vollständiger Abdruck der von der Fakultät für Biologie, Chemie und Geowissenschaften der Universität Bayreuth genehmigten Dissertation zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) Promotionsgesuch eingereicht am: 21. Oktober 2009 Tag des wissenschaftlichen Kolloquiums: 19. März 2010 Prüfungsausschuss: Prof. Dr. Birgitta Wöhrl (Erste Gutachterin) Prof. Dr. Olaf Stemmann (Zweiter Gutachter) Prof. Dr. Matthias Ullmann (Vorsitzender) Prof. Dr. Franz X. Schmidt „Das Leben ist wert, gelebt zu werden, sagt die Kunst, die schönste Verführerin; das Leben ist wert, erkannt zu werden, sagt die Wissenschaft.“ Friedrich Nietzsche Table of contents Table of contents Table of contents .........................................................................................................................I! Zusammenfassung..................................................................................................................... II! Summary ..................................................................................................................................IV! 1! Introduction.......................................................................................................................... 1! 1.1! Foamy viruses ............................................................................................................... 1! 1.2! Virus and life cycle ....................................................................................................... 3! 1.3! Reverse transcriptases ................................................................................................... 6! 1.3.1! The polymerase domain of the PR-RT enzyme ...................................................... 8! 1.3.2! The RNase H domain of the PR-RT enzyme ........................................................ 10! 1.4! Retroviral proteases..................................................................................................... 12! 2! Objectives .......................................................................................................................... 14! 3! Synopsis ............................................................................................................................. 15! 3.1! Comparison of foamy virus PR-RT catalytic activities .............................................. 15! 3.2! Resistance of foamy virus against azidothymidine ..................................................... 18! 3.3! Regulation of protease activity in foamy viruses ........................................................ 22! 3.3.1! Transient dimerization of foamy virus protease.................................................... 22! 3.3.2! Activation of foamy virus protease by nucleic acid sequences............................. 24! 4! List of abbreviations .......................................................................................................... 28! 5! References.......................................................................................................................... 30! 6! List of publications ............................................................................................................ 37! 7! Publication A ..................................................................................................................... 41! 8! Publication B...................................................................................................................... 53! 9! Publication C...................................................................................................................... 63! 10! Publication D ..................................................................................................................... 73! 11! Publication E...................................................................................................................... 79! 12! Publication F ...................................................................................................................... 91! 13! Publication G ................................................................................................................... 101! 14! Acknowledgement ........................................................................................................... 123! 15! Erklärung.......................................................................................................................... 125! ! I Zusammenfassung Zusammenfassung Foamy Viren oder Spumaretroviren gehören zur Familie der Retroviridae, unterscheiden sich jedoch deutlich von allen übrigen Retroviren (Orthoretroviren). Das Genom in infektiösen Viren besteht aus DNA und nicht aus RNA. Zudem wird Pol, das Vorläuferprotein der viralen Enzyme, von einer eigenen mRNA unabhängig von Capsid- und Matrix-Proteinen translatiert. Schließlich bleibt die virale Protease mit der Reversen Transkriptase verbunden, während sich die Proteasen von Orthoretroviren selbst abspalten. Gereifte Spumaretroviren enthalten somit ein Protease-Reverse Transkriptase (PR-RT) Protein, das drei katalytische Aktivitäten vereint: Proteolyse, DNA Polymerisation and RNase H Aktivität. In dieser Arbeit wurden rekombinante PR-RTs von zwei verschiedenen Foamy Viren (dem Prototyp Foamy Virus und dem Simian Foamy Virus aus Makaken) gereinigt und miteinander verglichen. Unsere Ergebnisse zeigen, dass sich die enzymatischen Aktivitäten und die biophysikalischen Eigenschaften der beiden Proteine ähneln. Sie unterschieden sich jedoch bezüglich ihres Resistenzverhaltens gegenüber Azidothymidin. Dieser Nukleosidinhibitor ist in der Lage die Replikation von Foamy Viren zu hemmen, indem er die DNA Polymerisation terminiert. Während Prototyp Foamy Viren keine Resistenz gegen Azidothymidin entwickelten, gelang es, Azidothymidin-resistente Simian Foamy Viren zu isolieren. Vier Mutationen im Bereich der Reversen Transkriptase wurden identifiziert, die für diese Resistenz verantwortlich sind. Um den molekularen Mechanismus der Resistenz aufzuklären, wurden die entsprechenden rekombinanten PR-RT-Enzyme in vitro analysiert. Es wurde nachgewiesen, dass die Resistenz der Viren auf der Fähigkeit beruht, den bereits eingebauten Inhibitor mit Hilfe von ATP wieder zu entfernen. Obwohl retrovirale Proteasen nur als Homodimere aktiv sind, zeigten analytische Ultrazentrifugation und Größenausschlußchromatographie, dass die PR-RTs des Simian Foamy Virus aus Makaken und des Prototyp Foamy Virus in Lösung als inaktive Monomere vorlagen. Die dreidimensionale Struktur der separaten Protease-Domäne des Simian Foamy Virus wurde durch Kernspinresonanzspektroskopie bestimmt. Sie weist die typische Faltung einer Monomeruntereinheit anderer retroviraler Proteasen auf. Darüber hinaus belegten Messungen paramagnetischer Relaxationsverstärkungen der Protease-Domäne mittels Kernspinresonanzspektroskopie die Ausbildung von transienten Homodimeren. Diese Arbeit zeigt weiterhin, dass bestimmte purinreiche RNA-Sequenzen der Foamy Viren in der Lage sind, die Protease zu aktivieren. Chemische Analysen der entsprechenden RNA- Sekundärstrukturen deuteten auf die Ausbildung von charakteristischen Haarnadelschleifen- Strukturen hin. Retardations- und chemische Proteinquervernetzungsexperimente bewiesen II Zusammenfassung zudem die Ausbildung von stabilen PR-RT Dimeren in Gegenwart dieser RNA-Sequenzen. Auf Grundlage der vorgestellten in vitro Experimente wird ein Modell für den Ablauf des Zusammenbaus der Viruspartikel von Foamy Viren vorgeschlagen. III Summary Summary Foamy viruses or spumaretroviruses belong to the family of retroviridae but differ in several aspects from other retroviruses (orthoretroviruses). Viral particles contain DNA not RNA. The Pol protein, the precursor of the viral enzymes, is translated from a separate mRNA independently of the capsid and matrix proteins. The protease remains covalently bound to the reverse transcriptase, while in orthoretroviruses the protease is cleaved off autocatalytically. Thus, in mature spumaretroviruses a protease-reverse transcriptase protein (PR-RT) with three different catalytic activities is found: proteolysis, DNA polymerization and RNase H activity. In this work, the recombinant PR-RTs from the prototype foamy virus and a simian foamy virus isolate from macaques were purified and compared. The biophysical and enzymatic properties of the two enzymes were similar. However, their behavior towards the nucleoside inhibitor azidothymidine is different. This nucleoside analog inhibits the replication of foamy viruses by terminating polymerization. Prototype foamy virus was not able to develop resistance against azidothymidine, but we succeeded in the generation of an azidothymidine- resistant simian foamy virus. Up to four mutations within the reverse transcriptase were found to be necessary to confer high resistance against azidothymidine. To characterize the mechanism of resistance, the corresponding recombinant PR-RTs were investigated in vitro. The data reveal that the azidothymidine resistance is based on the excision of the incorporated
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