Functional characterisation of the N-terminal domain of polyomavirus large T antigen

Knoblich, Konstantin (2010). Functional characterisation of the N-terminal domain of polyomavirus large T antigen. University of Birmingham. Ph.D.

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Abstract

Although scientists have extensively researched the relationship between viral oncoproteins and cellular tumour suppressor proteins in recent years, the molecular interactions between these proteins is still poorly understood. It is the goal of this thesis to establish the key elements of specific interactions, in particular to characterise the interaction between the N-terminal part of the viral murine polyoma oncoprotein large T antigen (PyLTNT), and the cellular human regulator protein retinoblastoma (pRb). The homologous SV40 large T antigen protein has been studied thoroughly in recent decades, and has been associated with mesothelioma, osteosarcoma and brain tumours.However, the murine polyomavirus encodes for 154 additional amino acids that are rich in glycine and proline residues and could potentially play an important role towards cell transformation. Moreover, the polyoma virus protein has not been studied to this extent before, and structural and binding experiments conducted here reveal that it remains functional while natively unfolded. Nuclear Magnetic Resonance (NMR) spectroscopy was employed to characterise the protein's motional properties in its native state. A large part of the backbone residues was assigned, and regions interacting with pRb formed a localised structure. The determination of polyomavirus regions associated with retinoblastoma (PRAR) between residues 131 to 137 and to 181 have never been observed and represents a significant advance.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):