An investigation into sodium-iodide symporter (NIS) dimerisation and its impact on radioiodide uptake in thyroid cancer

Rebecca Thompson, Alice Fletcher, Hannah Nieto, Mohammed Alshahrani, Katie Brookes, Jonathan Wolf Mueller, Nick Fine, David Hodson, Martin Read, Kristien Boelaert, Vicki Smith, Christopher McCabe

Research output: Contribution to journalAbstractpeer-review


The thyroid’s ability to accumulate iodide via the sodium-iodide symporter
(NIS) is utilised to successfully treat most thyroid cancers with
radioiodide. However, approximately 25% of thyroid cancers lose
functional NIS expression and become unresponsive to radioiodide
therapy, resulting in a poorer prognosis. Our knowledge of NIS regulation
is limited, but as dimerisation of NIS has been proposed, we
sought to investigate NIS dimerisation and function.
A homology model of NIS structure was built based on the bacterial
protein vSGLT using the modeling platform Phyre2, to identify residues
potentially involved in dimerisation, which were mutated via
site-directed mutagenesis. Proximity ligation assays (PLA) were used
to assess dimerisation of wild-type and mutant NIS. Novel constructs
conjugated to fluorescent proteins (cerulean or citrine) were created
to further assess dimerisation using Fӧrster resonance energy transfer
Dimerisation of wild-type NIS was confirmed via PLA in both a
thyroid (SW1736) and non-thyroid (HeLa) cell line. Furthermore, FRET
increased in the presence of both fluorophore-conjugated NIS
constructs compared to single expression (1.52 ± 0.10 vs 1.08 ± 0.18,
P < 0.0001), validating dimerisation. We mutated five residues identified
from our homology model (D237A, Y242A, T243A, Q471A and
A525F), and two putative dimerisation motifs identified in the literature
(glycine- and leucine-zipper motifs). PLA suggested that all mutants
retained the ability to dimerise, indicating that dimerisation
involves multiple or as yet undiscovered residues.
NIS dimerisation has been conclusively demonstrated using two
discrete methodologies. Further work is ongoing to determine the
critical residues, cellular localisation and regulation of NIS dimerisation
and its impact on function.
Original languageEnglish
Article numberP2
Pages (from-to)5
Number of pages1
JournalThyroid Research
Volume10(Suppl 2)
Issue number5
Publication statusPublished - 19 Sept 2017
Event65th British Thyroid Association Annual Meeting - London, United Kingdom
Duration: 16 May 201716 May 2017


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