Structure and function of the proton channel OTOP1

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Abstract

OTOP1 belongs to the otopetrin family of membrane proteins that form proton channels in cells of diverse types. In mammals, OTOP1 is involved in sour transduction in taste cells and contributes to otoconia formation in the inner ear. From the structural point of view, otopetrins, including OTOP1, represent a quasi-tetramer consisting of four α-barrels. The exact transport pathways mediating proton flux through the OTOP1 channel and gating units modulating its activity are still a matter of debate. This review discusses current data on structural and functional features of OTOP1. Suggested proton transport pathways, regulatory mechanisms, and key amino acid residues determining functionality of the otopetrins are considered. The existing kinetic models of OTOP1 are discussed as well. Based on revealed functional properties, OTOP1 is suggested to operate as a logical XOR element that allows for proton flux only if transmembrane pH gradient exists.

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About the authors

K. D. Sladkov

Institute of Cell Biophysics, Russian Academy of Sciences, FRC PSCBR RAS

Author for correspondence.
Email: klimitrich@ya.ru
Russian Federation, Pushchino, Moscow oblast, 142290

S. S. Kolesnikov

Institute of Cell Biophysics, Russian Academy of Sciences, FRC PSCBR RAS

Email: klimitrich@ya.ru
Russian Federation, Pushchino, Moscow oblast, 142290

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Supplementary files

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2. Fig. 1 Responses of HEK-293 cells expressing mouse (a), human (b), chicken (c), or zebrafish (d) OTOP1 to application of a pHi 5.5 or pHi 8.1 stimulus as shown in (a) (modified from [20] under a Creative Commons Attribution 4.0 International License).

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3. Fig. 2. Conductance of the OTOP1 channel expressed in HEK-293 at different transmembrane proton gradients. Data for acidic and alkaline stimuli [21] and NH4+ stimuli [20] were obtained by dividing the peak current by the proton-motive force [21].

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4. Fig. 3. a – OTOP1 contains 12 transmembrane helices. b – Schematic representation of the α-barrels formed by the helices and the loops connecting transmembrane helices 5–6 (shown in red) and 11–12 (shown in purple).

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5. Fig. 4. The structure of OTOP1 (view from the outside of the membrane). Possible proton transport pathways are marked with numbers 1–9. As shown in [30], pathways 4–6 are closed by cholesterol molecules, while the remaining pathways form water chains.

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6. Fig. 5. Amino acids, point mutations in which lead to changes in the function of the OTOP1 channel, are highlighted in color. Amino acid residues highlighted in red lead to the disappearance of currents initiated by acidic stimuli, and those highlighted in blue – by alkaline stimuli. Residues highlighted in pink modulate responses to acidic stimuli, and those highlighted in purple change the level of protein expression.

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7. Fig. 6. Time constants of activation of current through OTOP1 initiated by stimuli with different pH.

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