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Regulation of the transient receptor potential channel TRPA1 by its N-terminal ankyrin repeat domain
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SYSNO ASEP 0381621 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Regulation of the transient receptor potential channel TRPA1 by its N-terminal ankyrin repeat domain Author(s) Zayats, Vasilina (UEK-B) RID, SAI, ORCID
Samad, Abdul (UEK-B)
Minofar, Babak (UEK-B) RID
Roelofs, K. E. (US)
Stockner, T. (AT)
Ettrich, Rüdiger (UEK-B) RID, ORCID, SAINumber of authors 6 Source Title Journal of Molecular Modeling. - : Springer - ISSN 1610-2940
Roč. 19, č. 11 (2012), s. 4689-4700Number of pages 12 s. Language eng - English Country CZ - Czech Republic Keywords ankyrin repeat ; EF-hand ; familial episodic pain syndrom ; TRPA1 Subject RIV CE - Biochemistry R&D Projects GAP207/10/1934 GA ČR - Czech Science Foundation (CSF) CEZ AV0Z60870520 - UEK-B (2005-2011) UT WOS 000326193200009 EID SCOPUS 84888289833 DOI 10.1007/s00894-012-1505-1 Annotation 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. Workplace Global Change Research Institute Contact Nikola Šviková, svikova.n@czechglobe.cz, Tel.: 511 192 268 Year of Publishing 2014
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