Self-association of adenovirus 5 E1B-55 kDa as well as p53 is essential for their mutual interaction

Self-association of adenovirus 5 E1B-55 kDa as well as p53 is essential for their mutual interaction

Morawska-Onyszczuk, Magdalena

Dissertation

Angenommen am: 2009-12-14

Erschienen: 2009-12-15

Betreuer: Dobbelstein, Matthias Prof. Dr.

Gutachter: Melchior, Frauke Prof. Dr.

Gutachter: Wahl, Markus Prof. Dr.

Zum Verlinken/Zitieren: http://hdl.handle.net/11858/00-1735-0000-0006-B508-A

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Name: morawska_onyszczuk.pdf

Größe: 4,0 MB

Format: PDF

Beschreibung: Dissertation

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Zusammenfassung

Englisch

P53 is at the center of the control systems that mediate the response to DNA damage, leading to cell cycle arrest or apoptosis. Virus infection can cause a DNA damage response through virus replication intermediates, but many viruses have evolved mechanisms to interfere with this response. The adenovirus type 5 E1B-55 kDa oncoprotein has several known functions during the viral life cycle, but it is mostly known for its ability to bind and inactivate the tumor suppressor p53. Together with another viral protein, E4orf6, E1B-55 kDa joins an E3 ubiquitin ligase complex and marks p53 for proteasomal degradation. In the absence of viral binding partners, E1B-55 kDa forms cytoplasmic clusters and sequesters p53 to them. Interestingly, E1B-55 kDa and p53 are each capable of forming oligomers. We mapped the oligomerization domain of E1B-55 kDa to the central portion of the protein. Disturbing E1B-55 kDa self-association by point mutations at residues 285/286 or 307 not only impairs its intracellular localization to the cytoplasmic clusters, but in addition its association with p53. Strikingly, tetramerization of p53 is also required for efficient association with E1B-55 kDa. Moreover, two different E1B-55 kDa mutants defective for p53 binding but proficient for oligomerization can trans-complement each other for p53 relocalization. We propose that the homo-oligomerization of each component enables the efficient interaction between E1B-55 kDa and p53 through increased avidity.

Keywords: p53; adenovirus; oligomerization; E1B-55 kDa