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

Abstract
Data availability
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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 found 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.

Data availability

cryo-EM data were deposited with the PDB and cryo-EM densiities were deposited with the Electron Microscopy databank

The following data sets were generated

(2020) Cryo-EM structure of a dimer of decameric human CALHM4 in the absence of Ca2+
Protein Data Bank, 6YTK.

https://www.rcsb.org/structure/6YTK
(2020) Cryo-EM structure of a dimer of undecameric human CALHM4 in the absence of Ca2+
Protein Data Bank, 6YTL.

https://www.rcsb.org/structure/6YTL
(2020) Cryo-EM structure of a dimer of decameric human CALHM4 in the presence of Ca2+
Protein Data Bank, 6YTO.

https://www.rcsb.org/structure/6YTO
(2020) Cryo-EM structure of a dimer of undecameric human CALHM4 in the presence of Ca2+
Protein Data Bank, 6YTQ.

https://www.rcsb.org/structure/6YTQ
(2020) Cryo-EM structure of decameric human CALHM6 in the presence of Ca2+
Protein Data Bank, 6YTV.

https://www.rcsb.org/structure/6YTV
(2020) Cryo-EM structure of undecameric human CALHM6 in the presence of Ca2+
Protein Data Bank, 6YTX.

https://www.rcsb.org/structure/6YTX
(2020) Cryo-EM structure of a dimer of decameric human CALHM4 in the absence of Ca2+
EMDataBank, 10917.

https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-10917
(2020) Cryo-EM structure of a dimer of undecameric human CALHM4 in the absence of Ca2+
EMDataBank, 10919.

https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-10919
(2020) Cryo-EM structure of a dimer of decameric human CALHM4 in the presence of Ca2+
EMDataBank, 10920.

https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-10920
(2020) Cryo-EM structure of a dimer of undecameric human CALHM4 in the presence of Ca2+
EMDataBank, 10921.

https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-10921
(2020) Cryo-EM structure of decameric human CALHM6 in the presence of Ca2+
EMDataBank, 10924.

https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-10924
(2020) Cryo-EM structure of undecameric human CALHM6 in the presence of Ca2+
EMDataBank, 10925.

https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-10925

Article and author information

Author details

Katarzyna Drożdżyk

Department of Biochemistry, University of Zürich, Zürich, Switzerland

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6288-4735
Marta Sawicka

Department of Biochemistry, University of Zürich, Zürich, Switzerland

For correspondence
m.sawicka@bioc.uzh.ch

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4589-4290
Maria-Isabel Bahamonde-Santos

Department of Biochemistry, University of Zürich, Zürich, Switzerland

Competing interests
The authors declare that no competing interests exist.
Zaugg Jonas

Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland

Competing interests
The authors declare that no competing interests exist.
Dawid Deneka

Department of Biochemistry, University of Zürich, Zürich, Switzerland

Competing interests
The authors declare that no competing interests exist.
Christiane Albrecht

Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland

Competing interests
The authors declare that no competing interests exist.
Raimund Dutzler

Department of Biochemistry, University of Zürich, Zürich, Switzerland

For correspondence
dutzler@bioc.uzh.ch

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2193-6129

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_163421)

Raimund Dutzler

Stiftung Lindenhof Bern

Christiane Albrecht

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Human placental tissues were collected from the Division of Obstetrics and Gynecology, Lindenhofgruppe Bern, Switzerland, under approval by the ethical commission of the Canton of Bern (approval No Basec 2016-00250). Written informed consent was obtained from all participants.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.