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TitleCryo-EM structures of human ZnT8 in both outward- and inward-facing conformations.
Journal, issue, pagesElife, Vol. 9, Year 2020
Publish dateJul 29, 2020
AuthorsJing Xue / Tian Xie / Weizhong Zeng / Youxing Jiang / Xiao-Chen Bai /
PubMed AbstractZnT8 is a Zn/H antiporter that belongs to SLC30 family and plays an essential role in regulating Zn accumulation in the insulin secretory granules of pancreatic β cells. However, the Zn/H exchange ...ZnT8 is a Zn/H antiporter that belongs to SLC30 family and plays an essential role in regulating Zn accumulation in the insulin secretory granules of pancreatic β cells. However, the Zn/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 Zn binding sites within each subunit: a highly conserved primary site in transmembrane domain (TMD) housing the Zn substrate; an interfacial site between TMD and C-terminal domain (CTD) that modulates the Zn 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 Zn site during the transport cycle. Collectively, our studies provide the structural insights into the Zn/H exchange mechanism of HsZnT8.
External linksElife / PubMed:32723473 / PubMed Central
MethodsEM (single particle)
Resolution3.8 - 5.9 Å
Structure data

EMDB-22285, PDB-6xpd:
Cryo-EM structure of human ZnT8 double mutant - D110N and D224N, determined in outward-facing conformation
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-22286, PDB-6xpe:
Cryo-EM structure of human ZnT8 WT, in the presence of zinc, determined in outward-facing conformation
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-22287, PDB-6xpf:
Cryo-EM structure of human ZnT8 WT, in the absence of zinc, determined in heterogeneous conformations- one subunit in an inward-facing and the other in an outward-facing conformation
Method: EM (single particle) / Resolution: 5.9 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / ZnT8 / zinc transporter

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