1/25/2024 0 Comments Outward mapZnT8 has been shown to be one of the major autoantigens in type 1 diabetes ( Wenzlau et al., 2007), and autoantibodies against ZnT8 (ZnT8A) can be detected in ~70% of young patients with type 1 diabetes ( Kawasaki, 2012). Indeed, the aberrant function of ZnT8 is linked to both type 1 and 2 diabetes ( Chabosseau and Rutter, 2016). ZnT8 knock-out in mice leads to severe defects in insulin processing, storage and secretion as well as glucose tolerance, indicating its critical role in β-cell function and glucose metabolism ( Pound et al., 2009 Wijesekara et al., 2010). ZnT8, one of the 10 ZnTs that have been identified so far ( Chimienti et al., 2004), is localized in the insulin secretory granules of pancreatic β cells and responsible for the accumulation of high level of zinc inside granules, which is required for the packing of insulin in the hexameric form ( Davidson et al., 2014). ZIPs mediate the Zn 2+ uptake either from the extracellular space or organelle into cytosolic space, whereas ZnTs transport Zn 2+ in the opposite direction. In humans, the intracellular level of zinc is tightly regulated by two major Zn 2+ transporter families, the SLC39 (ZIPs) family and the SLC30 (ZnTs) family ( Eide, 2006). Not surprisingly, Zn 2+ deficiency can lead to a variety of disabling human diseases, such as diabetes, cancer and Alzheimer’s disease ( Prasad, 2013). Zn 2+, as a structural and catalytic cofactor, plays crucial roles in regulating protein functions, and thereby is essential for many cellular processes, including cell development and immunological functions ( Maret, 2013). Collectively, our studies provide the structural insights into the Zn 2+/H + exchange mechanism of HsZnT8. A comparison of the outward- and inward-facing structures reveals that the TMD of each HsZnT8 subunit undergoes a large structural rearrangement, allowing for alternating access to the primary Zn 2+ site during the transport cycle. HsZnT8 forms a dimeric structure with four Zn 2+ binding sites within each subunit: a highly conserved primary site in transmembrane domain (TMD) housing the Zn 2+ substrate an interfacial site between TMD and C-terminal domain (CTD) that modulates the Zn 2+ transport activity of HsZnT8 and two adjacent sites buried in the cytosolic domain and chelated by conserved residues from CTD and the His-Cys-His (HCH) motif from the N-terminal segment of the neighboring subunit. Here, we report the cryo-EM structures of human ZnT8 (HsZnT8) in both outward- and inward-facing conformations. However, the Zn 2+/H + exchange mechanism of ZnT8 remains unclear due to the lack of high-resolution structures. Levant has many Loot Containers scattered around the city.ZnT8 is a Zn 2+/H + antiporter that belongs to SLC30 family and plays an essential role in regulating Zn 2+ accumulation in the insulin secretory granules of pancreatic β cells.
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