An investigation into the dimerisation of the sodium-iodide symporter

Thompson, Rebecca Jane (2019). An investigation into the dimerisation of the sodium-iodide symporter. University of Birmingham. Ph.D.

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Abstract

The active accumulation of iodide into the thyroid, mediated by the sodium-iodide symporter (NIS), is vital for thyroid hormone production, which is essential for neurological development and metabolism throughout life. This system is the target of thyroid cancer treatment post-surgery, as NIS facilitates radioiodide uptake into, and subsequent ablation of, cancer cells. While this is a largely successful therapy, it is ineffective in patients with radioiodide-refractory thyroid cancers due to the loss of functional NIS. Unfortunately, the lack of alternative treatment options for these patients results in an extremely poor prognosis. Consequently, it is of great interest to improve our understanding of NIS regulation, with the ultimate clinical aim of re-introducing functional NIS expression in such patients to enable successful treatment with radioiodide. Since dimerisation is important for the function of many membrane proteins, it is significant that NIS has been suggested to exist at higher molecular weights indicative of dimerisation, although this has not been explored in depth. This thesis demonstrated the occurrence of NIS dimerisation using three distinct methodologies. Although investigations revealed that previously proposed motifs are unlikely to be involved in NIS dimerisation, an alternative role in protein folding was offered for these motifs. Consequently, a novel homology model of NIS dimerisation was created based on the dimeric crystal structure of the family member protein vSGLT, which revealed a putative dimerisation interface. Mutational studies demonstrated that interactions between residues Q471, Y242 and T243 mediate NIS dimerisation and suggested that dimerisation might be involved in protein trafficking.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):