biostudies-literatureUnknown10(17)Sun CCellular zinc (Zn²⁺) homeostasis is essential to human health and is under tight regulations. Human zinc transporter 1 (hZnT1) is a plasma membrane-localized Zn²⁺ exporter belonging to the ZnT family, and its functional aberration is associated with multiple diseases. Here, we show that hZnT1 works as a Zn²⁺/Ca²⁺ exchanger. We determine the structure of hZnT1 using cryo-electron microscopy (cryo-EM) single particle analysis. hZnT1 adopts a homodimeric structure, and each subunit contains a transmembrane domain consisting of six transmembrane segments, a cytosolic domain, and an extracellular domain. The transmembrane region displays an outward-facing conformation. On the basis of structural and functional analysis, we propose a model for the hZnT1-mediated Zn²⁺/Ca²⁺ exchange. Together, these results facilitate our understanding of the biological functions of hZnT1 and provide a basis for further investigations of the ZnT family transporters.Science advanceseadk5128https://www.ebi.ac.uk/biostudies/studies/S-EPMC11051671biostudies-literatureStructural insights into the calcium-coupled zinc export of human ZnT1.PMC11051671Liu XSun LSun CGao YWang XHe BfalseStructural insights into the calcium-coupled zinc export of human ZnT1.Cellular zinc (Zn²⁺) homeostasis is essential to human health and is under tight regulations. Human zinc transporter 1 (hZnT1) is a plasma membrane-localized Zn²⁺ exporter belonging to the ZnT family, and its functional aberration is associated with multiple diseases. Here, we show that hZnT1 works as a Zn²⁺/Ca²⁺ exchanger. We determine the structure of hZnT1 using cryo-electron microscopy (cryo-EM) single particle analysis. hZnT1 adopts a homodimeric structure, and each subunit contains a transmembrane domain consisting of six transmembrane segments, a cytosolic domain, and an extracellular domain. The transmembrane region displays an outward-facing conformation. On the basis of structural and functional analysis, we propose a model for the hZnT1-mediated Zn²⁺/Ca²⁺ exchange. Together, these results facilitate our understanding of the biological functions of hZnT1 and provide a basis for further investigations of the ZnT family transporters.2024-01-01T00:00:00Z2024 Apr2026-06-01T21:18:11.901Z2026-05-21T03:08:04.917ZS-EPMC110516713866933310.1126/sciadv.adk5128