Transmembrane 163 (TMEM163) Protein: A New Member of the Zinc Efflux Transporter Family

A growing body of evidence continues to demonstrate the vital roles that zinc and its transporters play on human health. The mammalian solute carrier 30 (SLC30) family, with ten current members, controls zinc efflux transport in cells. TMEM163, a recently reported zinc transporter, has similar characteristics in both predicted transmembrane domain structure and function to the cation diffusion facilitator (CDF) protein superfamily. This review discusses past and present data indicating that TMEM163 is a zinc binding protein that transports zinc in cells. We provide a brief background on TMEM163’s discovery, transport feature, protein interactome, and similarities, as well as differences, with known SLC30 (ZnT) protein family. We also examine recent reports that implicate TMEM163 directly or indirectly in various human diseases such as Parkinson’s disease, Mucolipidosis type IV and diabetes. Overall, the role of TMEM163 protein in zinc metabolism is beginning to be realized, and based on current evidence, we propose that it is likely a new CDF member belonging to mammalian SLC30 (ZnT) zinc efflux transporter proteins.

Transmembrane 163 (TMEM163) Protein: A New Member of the Zinc Efflux Transporter Family

A growing body of evidence continues to demonstrate the vital roles that zinc and its transporters play on human health. The solute carrier (SLC) 30 and 39 families, with ten and fourteen members, respectively, control zinc transport in cells. TMEM163, a recently characterized zinc transporter, has similar characteristics in both structure and function to the SLC30 family. This review examines recent data that reveal TMEM163 to be a zinc efflux transporter and a new member of the cation diffusion facilitator (CDF) family of mammalian zinc transporter (ZNT) proteins. It also discusses reports that implicate TMEM163 in various human diseases.

Cryo-EM structures of human ZnT8 in both outward- and inward-facing conformations

ZnT8 is a Zn2+/H+ antiporter that belongs to SLC30 family and plays an essential role in regulating Zn2+ accumulation in the insulin secretory granules of pancreatic β cells. However, the Zn2+/H+ exchange mechanism of ZnT8 remains unclear due to the lack of high-resolution structures. Here, we report the cryo-EM structures of human ZnT8 (HsZnT8) in both outward- and inward-facing conformations. HsZnT8 forms a dimeric structure with four Zn2+ binding sites within each subunit: a highly conserved primary site in transmembrane domain (TMD) housing the Zn2+ substrate; an interfacial site between TMD and C-terminal domain (CTD) that modulates the Zn2+ 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. 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 Zn2+ site during the transport cycle. Collectively, our studies provide the structural insights into the Zn2+/H+ exchange mechanism of HsZnT8.