University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

RNA Therapeutics Institute

Publication Date

2019-11-27

Document Type

Article Preprint

Disciplines

Amino Acids, Peptides, and Proteins | Biophysics | Molecular Biology | Structural Biology

Abstract

Biological membranes of many tissues and organs contain large-pore channels designed to permeate a wide variety of ions and metabolites. Examples include connexin, innexin, and pannexin, which form gap junctions and/or bona fide cell surface channels. The most recently identified large-pore channels are the calcium homeostasis modulators (CALHMs), which permeate ions and ATP in a voltage-dependent manner to control neuronal excitability, taste signaling, and pathologies of depression and Alzheimer’s disease. Despite such critical biological roles, the structures and patterns of oligomeric assembly remain unclear. Here, we reveal the first structures of two CALHMs, CALHM1 and CALHM2, by single particle cryo-electron microscopy, which show novel assembly of the four transmembrane helices into channels of 8-mers and 11-mers, respectively. Furthermore, molecular dynamics simulations suggest that lipids can favorably assemble into a bilayer within the larger CALHM2 pore, but not within CALHM1, demonstrating the potential correlation between pore-size, lipid accommodation, and channel activity.

Keywords

calcium homeostasis modulator proteins (CALHMs), large-pore channels, lipids, Biophysics

Rights and Permissions

The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-ND 4.0 International license.

DOI of Published Version

10.1101/857698

Source

bioRxiv 857698; doi: https://doi.org/10.1101/857698. Link to preprint on bioRxiv service.

Related Resources

Now published in Nature Structural & Molecular Biology doi: 10.1038/s41594-019-0369-9

Journal/Book/Conference Title

bioRxiv

Creative Commons License

Creative Commons Attribution-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-No Derivative Works 4.0 License.

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