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Open AccessArticle

C-Terminal Domain of the Human Zinc Transporter hZnT8 Is Structurally Indistinguishable from Its Disease Risk Variant (R325W)

1
Drug Discovery and Structural Biology group, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad 44000, Pakistan
2
Structural Biology Laboratory, Elettra-Sincrotrone Trieste, 34149 Trieste, Italy
3
Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(3), 926; https://doi.org/10.3390/ijms21030926
Received: 10 December 2019 / Revised: 17 January 2020 / Accepted: 19 January 2020 / Published: 31 January 2020
(This article belongs to the Collection Feature Papers in Molecular Biophysics)
The human zinc transporter 8 (hZnT8) plays important roles in the storage of insulin in the secretory vesicles of pancreatic β cells. hZnT8 consists of a transmembrane domain, with its N- and C-termini protruding into the cytoplasm. Interestingly, the exchange of arginine to tryptophan at position 325 in the C-terminal domain (CTD) increases the risk of developing type 2 diabetes mellitus (T2D). In the present study, the CTDs of hZnT8 (the wild-type (WT) and its disease risk variant (R325W)) were expressed, purified, and characterized in their native forms by biophysical techniques. The data reveal that the CTDs form tetramers which are stabilized by zinc binding, and exhibit negligible differences in their secondary structure content and zinc-binding affinities in solution. These findings provide the basis for conducting further structural studies aimed at unravelling the molecular mechanism underlying the increased susceptibility to develop T2D, which is modulated by the disease risk variant. View Full-Text
Keywords: human zinc transporter hZnT8; C-terminal domain; disease risk variant; biophysical characterization human zinc transporter hZnT8; C-terminal domain; disease risk variant; biophysical characterization
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MDPI and ACS Style

Ullah, R.; Shehzad, A.; Shah, M.A.; March, M.D.; Ismat, F.; Iqbal, M.; Onesti, S.; Rahman, M.; McPherson, M.J. C-Terminal Domain of the Human Zinc Transporter hZnT8 Is Structurally Indistinguishable from Its Disease Risk Variant (R325W). Int. J. Mol. Sci. 2020, 21, 926.

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