Structure and function of the PLK1-EBNA2 protein complex in B-lymphocytes

Tsoneva, Viktoria (2021): Structure and function of the PLK1-EBNA2 protein complex in B-lymphocytes. Dissertation, LMU München: Medizinische Fakultät

Abstract

Our research group has discovered that Epstein-Barr virus nuclear antigen 2 (EBNA2) can form a protein complex with the Polo-like-Kinase 1 (PLK1). Consequently, we aimed to exploit the structural and functional insights of this interaction in order to improve our comprehension of the development of Epstein-Barr-Virus infection. In this dissertation project, the interaction of PLK1 with EBNA2 was confirmed and thoroughly examined through the application of various biochemical and molecular approaches with a focus on the question of whether the EBNA2-PLK1 protein complex supports the transformation of B-lymphocytes.The PLK1 ATP-competitive kinase inhibitor Volasertib does not inhibit EBNA2/PLK1 complex formation. Both active and inactive PLK1 can bind to EBNA2. Comparing the toxicity and efficacy levels of PLK1 inhibition in EBNA2 positive and negative cell lines showed that EBV infected B-cells are sensitive to Volasertib treatment and more importantly, EBNA2 sensitises EBV-negative B-cell lines to Volasertib treatment. We were able to demonstrate that the CR7 domain is essential, but not alone responsible for the binding of EBNA2 to PLK1. On the contrary, PLK1 appears to have more than one binding site for the interaction with EBNA2. Both, the polo-box domain and the kinase domain of PLK1 can bind efficiently to EBNA2. Theis study is only a foundation for further work. The identification of PLK1 as an EBNA2 interaction partner suggests the characterisation of regulatory correlated pathways to elucidate the exact importance of this protein complex for the pathological molecular mechanisms of tumourigenesis in an attempt to contribute to the future development of oncological treatments.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Epstein-Barr-Virus, EBV, PLK1, EBNA2, Volasertib, Tumor
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 28. Oktober 2021
• 1. Bericht­erstatter:in: Spiekermann, Karsten