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

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 expre...

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Bibliographic Details
Published in:eLife 2020-05, Vol.9
Main Authors: Drożdżyk, Katarzyna, Sawicka, Marta, Bahamonde-Santos, Maria-Isabel, Jonas, Zaugg, Deneka, Dawid, Albrecht, Christiane, Dutzler, Raimund
Format: Article
Language:English
Subjects:
Analysis
Calcium channels
Calcium channels (voltage-gated)
Calcium Channels - genetics
Calcium Channels - metabolism
Calcium Channels - ultrastructure
Calcium homeostasis
CALHM channels
Chemical properties
Control
cryo-electron microscopy
Cryoelectron Microscopy
Electrophysiology
Female
Fetuses
Genes
HEK293 Cells
Homeostasis
Humans
Investigations
Lipids
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Membrane Glycoproteins - ultrastructure
Membrane Lipids - metabolism
Membrane Potentials
Models, Molecular
Physiology
Placenta
Placenta - metabolism
Placenta - ultrastructure
Pregnancy
Protein Conformation
Proteins
Structural Biology and Molecular Biophysics
Structure
Structure-Activity Relationship
Transcription
transcription analysis
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.55853