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UBC Theses and Dissertations

Probing the interactions between U24 from HHV-6B and hNedd4L WW and Fyn-SH3 domains Pi, Keng-Shuo


Multiple sclerosis (MS) is neurological inflammatory disease in the central nervous system (CNS) that affects every 1 in 400 people in Canada. Although it was first characterized over a century ago, the cause of MS remains elusive, as does consequently a cure. Many factors have been identified as possible triggers, including viruses such as the highly prevalent and latent human herpes virus type 6 (HHV-6) – a member of the Roseolovirus family. There are two variants of this virus, namely HHV-6A and -6B, and the protein U24, encoded in both forms, has been found to be implicated in multiple sclerosis. This thesis describes the study of the binding interaction of U24 from HHV-6B (U24-6B) and two protein binding partners: the WW3* domain from human Neural precursor cell expressed developmentally down-regulated protein 4 like (hNedd4L-WW3*) and the SH3 domain from Fyn tyrosine kinase (Fyn-SH3). These interactions help to further define U24s’ function. Previous studies have suggested that U24 from HHV-6A (U24-6A) and HHV-7 are involved in endocytic recycling of key T-cell receptors, a process mediated by WW domains. Moreover, earlier work has shown that U24-6A may be involved in triggering an autoimmune reaction in MS, through its molecular mimicry of myelin basic protein (MBP), a protein that interacts with Fyn-SH3. None of this previous research investigated whether U24-6B, which is highly homologous to U24-6A, functions in the same way. Hence this thesis aims to fill in this knowledge gap. The interaction between U24-6B and hNedd4L-WW3* was investigated using isothermal titration calorimetry (ITC). The effect of the post-translational modification of phosphorylation at residue Thr6 was also probed. The interaction between U24-6B and Fyn-SH3 was characterized using nuclear magnetic resonance (NMR) spectroscopy. Both these studies shed further insight into the function of U24 from Roseolovirus and its potential role in MS.

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