Publikationsserver der Universitätsbibliothek Marburg

Titel:Die Funktion der Coiled-Coil-Domäne im Nukleoprotein des Ebolavirus
Autor:Behrendt, Katja
Weitere Beteiligte: Becker, Stephan (Prof. Dr.)
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2012/1027
DOI: https://doi.org/10.17192/z2012.1027
URN: urn:nbn:de:hebis:04-z2012-10271
DDC: Medizin
Titel (trans.):Function of the coiled coil domain of the Ebolavirus nucleoprotein
Publikationsdatum:2012-12-17
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Coiled coil, Nukleoprotein, Self assembly, Ebola-Virus, Nucleocapsid, Nucleoprotein, Self assembly

Zusammenfassung:
Das Ebolavirus (EBOV) bildet mit dem Marburgvirus die Familie der Filoviren, die aufgrund ihres einzelsträngigen, negativ orientierten RNA-Genoms der Ordnung der Mononegavirales zugeteilt werden. Filoviren verursachen beim Menschen und bei nicht-menschlichen Primaten ein schweres hämorrhagisches Fieber mit einer Mortalitätsrate bis zu 90%. Deshalb und weil es bisher keine spezifische Therapie und keine Impfung gibt, werden Filoviren als Pathogene der Sicherheitsstufe 4 eingestuft. Der Nukleokapsidkomplex des EBOV besteht aus dem nicht-segmentierten RNAGenom sowie dem Nukleokapsidprotein NP, der viralen Polymerase L, dem Polymerase-Ko-Faktor VP35 sowie VP30 besteht. Gegenstand dieser Arbeit ist eine Coiled-Coil-Domäne innerhalb des NP, deren Einfluss auf verschiedene Funktionen des NP untersucht werden sollte. Hierfür wurde die Rolle der Coiled-Coil bei der Interaktion mit VP30 und VP35 analysiert. NPMutanten, die entweder keine Coiled-Coil-3D-Struktur oder gar keine Coiled-Coil mehr aufwiesen, konnten hier zwar noch mit VP35, aber nicht mehr mit VP30 interagieren. Die Gründe hierfür sind vermutlich, dass VP35 mehrere Bindungsstellen besitzt und VP30 entweder im Bereich der Coiled-Coilbindet oder die durch die Coiled-Coil vermittelte Konformation des NP benötigt. Weiterhin befasst sich diese Arbeit mit der Rolle der Coiled-Coil-Domäne bei der NPNP- Interaktion und dem self assembly. Immunfluoreszenzanalysen ergaben, dass die Bildung von NP-Einschlusskörpern, so genannter inclusions, von der Coiled-Coil- Domäne abhängt. Coiled-Coil-defiziente Mutanten können aber noch durch NPwt in inclusions rekrutiert werden, die Fähigkeit zur Selbstinteraktion ist also nur eingeschränkt. Mittels eines Complementation Assays konnte gezeigt werden, dass die Coiled-Coil-Domäne allein ausreichend für eine NP-NP Bindung sein kann. Immunelektronenmikroskopischen Analysen konnten zudem zeigen, dass die Bildung von NP-Helices, welche das Gerüst der Nukleokapside darstellen, ebenfalls nur bei intakter Coiled-Coil-Domäne oder in Gegenwart von NPwt möglich ist. Eine Rolle könnte hierbei entweder eine durch die Coiled-Coil-Domäne vermittelte Oligomerisierung des NP oder RNA-Interaktion spielen, welche zur Bildung von Helices wichtig ist. Im letzten Teil der Arbeit wurde der Einfluss Coiled-Coil-Domäne auf die virale Transkription untersucht. Hierbei zeigte sich im iVLP-Assay, dass eine nicht intakte Coiled-Coil einen dominant negativen Effekt auf die Transkription hat. Dies ist vermutlich dadurch bedingt, dass ohne intakte Coiled-Coil keine NP-Helices gebildet werden können und so auch keine regulären Nukleokapside, welche für die Polymerase als Matrize zur Transkription und Replikation dienen.

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