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bioRxiv · 10.1101/542308

Structures of the Otopetrin Proton Channels Otop1 and Otop3

Saotome, K.·Teng, B.·Tsui, C. C.·Lee, W.-H.·Tu, Y.-H.·Sansom, M. S. P.·Liman, E. R.·Ward, A. B.
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Abstract

Otopetrins (Otop1-Otop3) comprise one of only two known eukaryotic proton-selective channel families. Otop1 is required for formation of otoconia and is a candidate mammalian sour taste receptor. Here, we report cryo-EM structures of zebrafish Otop1 and chicken Otop3 in lipid nanodiscs. The structures reveal a dimeric architecture of Otopetrins with each subunit consisting of twelve transmembrane helices divided into structurally related N and C domains. Cholesterol-like molecules occupy various sites in Otop1 and Otop3 and occlude a cavernous central tunnel. Two hydrophilic vestibules, as well as the intrasubunit interface between N and C domains, form conduits for water entry into the membrane plane in molecular dynamics simulations, suggesting they each could provide pathways for proton conduction. We also demonstrate the functional relevance of a salt bridge in the C domain vestibule by mutagenesis. Our results provide a structural basis for understanding the function of the Otopetrin proton channel family.

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Saotome, K., Teng, B., Tsui, C. C., Lee, W.-H., Tu, Y.-H., Sansom, M. S. P., Liman, E. R., Ward, A. B.. 2019-02-06. Structures of the Otopetrin Proton Channels Otop1 and Otop3. https://doi.org/10.1101/542308

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