Cryo-EM structures and functional properties of CALHM channels of the human placenta

Elife. 2020 May 6;9:e55853. doi: 10.7554/eLife.55853.

Abstract

The transport of substances across the placenta is essential for the development of the fetus. Here, we were interested in the role of channels of the calcium homeostasis modulator (CALHM) family in the human placenta. By transcript analysis, we found the paralogs CALHM2, 4, and 6 to be highly expressed in this organ and upregulated during trophoblast differentiation. Based on electrophysiology, we observed that activation of these paralogs differs from the voltage- and calcium-gated channel CALHM1. Cryo-EM structures of CALHM4 display decameric and undecameric assemblies with large cylindrical pore, while in CALHM6 a conformational change has converted the pore shape into a conus that narrows at the intracellular side, thus describing distinct functional states of the channel. The pore geometry alters the distribution of lipids, which occupy the cylindrical pore of CALHM4 in a bilayer-like arrangement whereas they have redistributed in the conical pore of CALHM6 with potential functional consequences.

Keywords: CALHM channels; cryo-electron microscopy; electrophysiology; human; lipids; molecular biophysics; placenta; structural biology; transcription analysis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Channels / ultrastructure
  • Cryoelectron Microscopy*
  • Female
  • HEK293 Cells
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Glycoproteins / ultrastructure
  • Membrane Lipids / metabolism
  • Membrane Potentials
  • Models, Molecular
  • Placenta / metabolism*
  • Placenta / ultrastructure
  • Pregnancy
  • Protein Conformation
  • Structure-Activity Relationship

Substances

  • CALHM1 protein, human
  • CALHM2 protein, human
  • CALHM6 protein, human
  • Calcium Channels
  • Membrane Glycoproteins
  • Membrane Lipids

Associated data

  • PDB/6YTK
  • PDB/6YTL
  • PDB/6YTO
  • PDB/6YTQ
  • PDB/6YTV
  • PDB/6YTX