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The C-terminal cytosolic domain of the human zinc transporter ZnT8 and its diabetes risk variant

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The C-terminal cytosolic domain of the human zinc transporter ZnT8 and its diabetes risk variant. / Parsons, Douglas S.; Hogstrand, Christer; Maret, Wolfgang.

In: FEBS Journal, Vol. 285, No. 7, 04.2018, p. 1237-1250.

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Harvard

Parsons, DS, Hogstrand, C & Maret, W 2018, 'The C-terminal cytosolic domain of the human zinc transporter ZnT8 and its diabetes risk variant', FEBS Journal, vol. 285, no. 7, pp. 1237-1250. https://doi.org/10.1111/febs.14402

APA

Parsons, D. S., Hogstrand, C., & Maret, W. (2018). The C-terminal cytosolic domain of the human zinc transporter ZnT8 and its diabetes risk variant. FEBS Journal, 285(7), 1237-1250. https://doi.org/10.1111/febs.14402

Vancouver

Parsons DS, Hogstrand C, Maret W. The C-terminal cytosolic domain of the human zinc transporter ZnT8 and its diabetes risk variant. FEBS Journal. 2018 Apr;285(7):1237-1250. https://doi.org/10.1111/febs.14402

Author

Parsons, Douglas S. ; Hogstrand, Christer ; Maret, Wolfgang. / The C-terminal cytosolic domain of the human zinc transporter ZnT8 and its diabetes risk variant. In: FEBS Journal. 2018 ; Vol. 285, No. 7. pp. 1237-1250.

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@article{98b6b92030f9401cafce84ec1ea6fd47,
title = "The C-terminal cytosolic domain of the human zinc transporter ZnT8 and its diabetes risk variant",
abstract = "A significant aspect of the control of cellular zinc in eukarya is its subcellular re-distribution. One of the four human vesicular zinc transporters, ZnT8, supplies the millimolar zinc concentrations of insulin granules in pancreatic β-cells, affecting insulin processing, crystallisation and secretion. ZnT8 has a transmembrane and a C-terminal cytosolic domain; the latter has important functions and purportedly mediates protein-protein interactions, senses cytosolic zinc and/or channels zinc to the transport site in the transmembrane domain (TMD). A common variant W325R in the C-terminal domain (CTD) increases the risk to develop type 2 diabetes and affects autoantibody specificity in type 1 diabetes. To investigate the differences between the two protein variants, we purified and biophysically characterised both variants of the ZnT8 CTD [R325 variant of ZnT8 CTD (aa267-369) (ZnT8cR) and W325 variant of ZnT8 CTD (aa267-369) (ZnT8cW)]. The domains fold independently of the TMD. Remarkably, the ZnT8cW variant (diabetes protection in the full-length protein) is less thermostable than the ZnT8cR variant (diabetes risk in the full-length protein). The ZnT8cW monomers associate with higher affinity. Both CTD variants bind zinc with a stoichiometry that differs from bacterial homologues, emphasising the limitation of the latter as models for the structure and function of the human proteins. The relatively small but reproducible differences between the two ZnT8 CTD variants begin to provide a molecular basis for the different diabetes susceptibility caused by the full-length ZnT8 proteins.",
author = "Parsons, {Douglas S.} and Christer Hogstrand and Wolfgang Maret",
year = "2018",
month = apr,
doi = "10.1111/febs.14402",
language = "English",
volume = "285",
pages = "1237--1250",
journal = "FEBS Journal",
issn = "1742-464X",
number = "7",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - The C-terminal cytosolic domain of the human zinc transporter ZnT8 and its diabetes risk variant

AU - Parsons, Douglas S.

AU - Hogstrand, Christer

AU - Maret, Wolfgang

PY - 2018/4

Y1 - 2018/4

N2 - A significant aspect of the control of cellular zinc in eukarya is its subcellular re-distribution. One of the four human vesicular zinc transporters, ZnT8, supplies the millimolar zinc concentrations of insulin granules in pancreatic β-cells, affecting insulin processing, crystallisation and secretion. ZnT8 has a transmembrane and a C-terminal cytosolic domain; the latter has important functions and purportedly mediates protein-protein interactions, senses cytosolic zinc and/or channels zinc to the transport site in the transmembrane domain (TMD). A common variant W325R in the C-terminal domain (CTD) increases the risk to develop type 2 diabetes and affects autoantibody specificity in type 1 diabetes. To investigate the differences between the two protein variants, we purified and biophysically characterised both variants of the ZnT8 CTD [R325 variant of ZnT8 CTD (aa267-369) (ZnT8cR) and W325 variant of ZnT8 CTD (aa267-369) (ZnT8cW)]. The domains fold independently of the TMD. Remarkably, the ZnT8cW variant (diabetes protection in the full-length protein) is less thermostable than the ZnT8cR variant (diabetes risk in the full-length protein). The ZnT8cW monomers associate with higher affinity. Both CTD variants bind zinc with a stoichiometry that differs from bacterial homologues, emphasising the limitation of the latter as models for the structure and function of the human proteins. The relatively small but reproducible differences between the two ZnT8 CTD variants begin to provide a molecular basis for the different diabetes susceptibility caused by the full-length ZnT8 proteins.

AB - A significant aspect of the control of cellular zinc in eukarya is its subcellular re-distribution. One of the four human vesicular zinc transporters, ZnT8, supplies the millimolar zinc concentrations of insulin granules in pancreatic β-cells, affecting insulin processing, crystallisation and secretion. ZnT8 has a transmembrane and a C-terminal cytosolic domain; the latter has important functions and purportedly mediates protein-protein interactions, senses cytosolic zinc and/or channels zinc to the transport site in the transmembrane domain (TMD). A common variant W325R in the C-terminal domain (CTD) increases the risk to develop type 2 diabetes and affects autoantibody specificity in type 1 diabetes. To investigate the differences between the two protein variants, we purified and biophysically characterised both variants of the ZnT8 CTD [R325 variant of ZnT8 CTD (aa267-369) (ZnT8cR) and W325 variant of ZnT8 CTD (aa267-369) (ZnT8cW)]. The domains fold independently of the TMD. Remarkably, the ZnT8cW variant (diabetes protection in the full-length protein) is less thermostable than the ZnT8cR variant (diabetes risk in the full-length protein). The ZnT8cW monomers associate with higher affinity. Both CTD variants bind zinc with a stoichiometry that differs from bacterial homologues, emphasising the limitation of the latter as models for the structure and function of the human proteins. The relatively small but reproducible differences between the two ZnT8 CTD variants begin to provide a molecular basis for the different diabetes susceptibility caused by the full-length ZnT8 proteins.

U2 - 10.1111/febs.14402

DO - 10.1111/febs.14402

M3 - Article

VL - 285

SP - 1237

EP - 1250

JO - FEBS Journal

JF - FEBS Journal

SN - 1742-464X

IS - 7

ER -

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