Structural insights into the calcium-coupled zinc export of human ZnT1

Sci Adv. 2024 Apr 26;10(17):eadk5128. doi: 10.1126/sciadv.adk5128. Epub 2024 Apr 26.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport
  • Calcium* / metabolism
  • Cation Transport Proteins* / chemistry
  • Cation Transport Proteins* / metabolism
  • Cryoelectron Microscopy*
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Protein Domains
  • Protein Multimerization
  • Zinc* / chemistry
  • Zinc* / metabolism

Substances

  • Zinc
  • Cation Transport Proteins
  • SLC30A1 protein, human
  • Calcium