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Regulation of the transient receptor potential channel TRPA1 by its N-terminal ankyrin repeat domain

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Abstract

The transient receptor potential channel A1 (TRPA1) is unique among ion channels of higher vertebrates in that it harbors a large ankyrin repeat domain. The TRPA1 channel is expressed in the inner ear and in nociceptive neurons. It is involved in hearing as well as in the perception of pungent and irritant chemicals. The ankyrin repeat domain has special mechanical properties, which allows it to function as a soft spring that can be extended over a large range while maintaining structural integrity. A calcium-binding site has been experimentally identified within the ankyrin repeats. We built a model of the N-terminal 17 ankyrin repeat structure, including the calcium-binding EF-hand. In our simulations we find the calcium-bound state to be rigid as compared to the calcium-free state. While the end-to-end distance can change by almost 50% in the apo form, these fluctuations are strongly reduced by calcium binding. This increase in stiffness that constraints the end-to-end distance in the holo form is predicted to affect the force acting on the gate of the TRPA1 channel, thereby changing its open probability. Simulations of the transmembrane domain of TRPA1 show that residue N855, which has been associated with familial episodic pain syndrome, forms a strong link between the S4-S5 connecting helix and S1, thereby creating a direct force link between the N-terminus and the gate. The N855S mutation weakens this interaction, thereby reducing the communication between the N-terminus and the transmembrane part of TRPA1.

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Acknowledgments

We gratefully acknowledge support from the Ministry of Education, Youth and Sports of the Czech Republic (projects No. ME09062 and MSM6007665808), the Academy of Sciences of the Czech Republic (AVOZ60870520), and the Czech Science Foundation, grant P207/10/1934. VZ is supported by the University of South Bohemia, grant GAJU 170/2010/P. Access to the National Grid Infrastructure -MetaCentrum- is highly appreciated.

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Authors and Affiliations

  1. Institute of Nanobiology and Structural Biology of GCRC, Academy of Sciences of the Czech Republic, Zamek 136, 37333, Nove Hrady, Czech Republic

    Vasilina Zayats, Abdul Samad, Babak Minofar & Rudiger Ettrich

  2. Faculty of Sciences, University of South Bohemia in Ceske Budejovice, Zamek 136, 37333, Nove Hrady, Czech Republic

    Vasilina Zayats, Babak Minofar & Rudiger Ettrich

  3. Princeton University, Princeton, NJ, USA

    Katherine E. Roelofs

  4. Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Waehringerstrasse 13a, 1090, Vienna, Austria

    Thomas Stockner

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  1. Vasilina Zayats
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  2. Abdul Samad
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Correspondence to Thomas Stockner.

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Zayats, V., Samad, A., Minofar, B. et al. Regulation of the transient receptor potential channel TRPA1 by its N-terminal ankyrin repeat domain. J Mol Model 19, 4689–4700 (2013). https://doi.org/10.1007/s00894-012-1505-1

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