Cryo-EM structure of a eukaryotic zinc transporter at a low pH suggests its Zn 2+ -releasing mechanism

Zinc transporter 8 (ZnT8) is mainly expressed in pancreatic islet β cells and is responsible for H -coupled uptake (antiport) of Zn into the lumen of insulin secretory granules. Structures of human ZnT8 and its prokaryotic homolog YiiP have provided structural basis for constructing a plausible tran...

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Bibliographic Details
Published inJournal of structural biology Vol. 215; no. 1; p. 107926
Main Authors Zhang, Senfeng, Fu, Chunting, Luo, Yongbo, Xie, Qingrong, Xu, Tong, Sun, Ziyi, Su, Zhaoming, Zhou, Xiaoming
Format Journal Article
LanguageEnglish
Published United States 01.03.2023
Subjects
Cryoelectron Microscopy
Eukaryota
Humans
Hydrogen-Ion Concentration
Protons
Zinc
Membrane protein
SLC30
ZnT8
CDF
Single-particle reconstruction
Protonation
Transport cycle
Cryo-EM structure
Conformational change
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Summary:Zinc transporter 8 (ZnT8) is mainly expressed in pancreatic islet β cells and is responsible for H -coupled uptake (antiport) of Zn into the lumen of insulin secretory granules. Structures of human ZnT8 and its prokaryotic homolog YiiP have provided structural basis for constructing a plausible transport cycle for Zn . However, the mechanistic role that protons play in the transport process remains unclear. Here we present a lumen-facing cryo-EM structure of ZnT8 from Xenopus tropicalis (xtZnT8) in the presence of Zn at a luminal pH (5.5). Compared to a Zn -bound xtZnT8 structure at a cytosolic pH (7.5), the low-pH structure displays an empty transmembrane Zn -binding site with a disrupted coordination geometry. Combined with a Zn -binding assay our data suggest that protons may disrupt Zn coordination at the transmembrane Zn -binding site in the lumen-facing state, thus facilitating Zn release from ZnT8 into the lumen.
ISSN:1095-8657