Lipid-tuned Zinc Transport Activity of Human ZnT8 Protein Correlates with Risk for Type-2 Diabetes

摘要: 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 ions. A genetic variant human arising from single nonsynonymous nucleotide change contributes to increased susceptibility type-2 diabetes (T2D), but it remains unclear how high risk (Arg-325), which also higher frequency (>50%) allele, correlated with transport activity. Here, we compared activity Arg-325 that low (Trp-325). was found be more active than Trp-325 form following induced expression HEK293 We further examined functional consequences changing lipid conditions mimic impact remodeling on during granule biogenesis. Purified variants proteoliposomes exhibited 4-fold tunability by anionic phospholipids, lysophosphatidylcholine and cholesterol. Over broad range permissive compositions, consistently accelerated kinetics versus Trp-form. In agreement finding rare loss-of-function mutations are associated reduced T2D risk, our results suggested common hyperactive, thus may targeted inhibition reduce general populations.