Lipid-tuned Zinc Transport Activity of Human ZnT8 Protein Correlates with Risk for Type-2 Diabetes
| Autor: | Guy A. Rutter, Dax Fu, Chengfeng Merriman, Qiong Huang |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Nonsynonymous substitution medicine.medical_treatment Biochemistry chemistry.chemical_compound 0302 clinical medicine Insulin genetic polymorphism Cation Transport Proteins Phospholipids diabetes zinc 11 Medical And Health Sciences Cholesterol Lysophosphatidylcholine transporter YIIP 03 Chemical Sciences Life Sciences & Biomedicine Biochemistry & Molecular Biology membrane transporter reconstitution medicine.medical_specialty chemistry.chemical_element Papers of the Week Zinc Transporter 8 Zinc Biology drug discovery 03 medical and health sciences INSULIN SECRETORY GRANULES Internal medicine medicine Humans Allele Molecular Biology Science & Technology MUTATIONS HEK 293 cells Lysophosphatidylcholines Transporter Cell Biology 06 Biological Sciences MICE HEK293 Cells 030104 developmental biology Endocrinology Diabetes Mellitus Type 2 chemistry kinetics Mutation PANCREATIC BETA-CELLS GLUCOSE-HOMEOSTASIS 030217 neurology & neurosurgery |
| Zdroj: | Journal of Biological Chemistry. 291:26950-26957 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m116.764605 |
| Popis: | Zinc is a critical element for insulin storage in the secretory granules of pancreatic beta cells. The islet-specific zinc transporter ZnT8 mediates granular sequestration of zinc ions. A genetic variant of human ZnT8 arising from a single nonsynonymous nucleotide change contributes to increased susceptibility to type-2 diabetes (T2D), but it remains unclear how the high risk variant (Arg-325), which is also a higher frequency (>50%) allele, is correlated with zinc transport activity. Here, we compared the activity of Arg-325 with that of a low risk ZnT8 variant (Trp-325). The Arg-325 variant was found to be more active than the Trp-325 form following induced expression in HEK293 cells. We further examined the functional consequences of changing lipid conditions to mimic the impact of lipid remodeling on ZnT8 activity during insulin granule biogenesis. Purified ZnT8 variants in proteoliposomes exhibited more than 4-fold functional tunability by the anionic phospholipids, lysophosphatidylcholine and cholesterol. Over a broad range of permissive lipid compositions, the Arg-325 variant consistently exhibited accelerated zinc transport kinetics versus the Trp-form. In agreement with the human genetic finding that rare loss-of-function mutations in ZnT8 are associated with reduced T2D risk, our results suggested that the common high risk Arg-325 variant is hyperactive, and thus may be targeted for inhibition to reduce T2D risk in the general populations. |
| Databáze: | OpenAIRE |
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