Cation translocation in human ORAI channels: Modeling and simulations

Vasilina Zayats,¹ Irene Frischauf,² Saurabh Kumar Pandey,^1,3 Isabella Derler,² Christoph Romanin,²   Rainer Schindl,² Rüdiger H. Ettrich^1,3

¹Center for Nanobiology and Structural Biology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Zamek 136, CZ-373 33 Nove Hrady, Czech Republic, ettrich@nh.cas.cz

²Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, Gruberstrasse 40, 4020 Linz, Austria

³Faculty of Sciences, University of South Bohemia, Zamek 136, CZ- 373 33 Nove Hrady, Czech Republic.

 

Ca²⁺-release-activated Ca²⁺ channels, encoded by Orai channels, form an ubiquitous cellular Ca²⁺ entry pathway, and control diverse signalling processes including gene expression, cell proliferation and T-cell activation. The human genome contains three Orai isoforms; however it remains unknown if their sequence variations are required for specific Ca²⁺ signals. Orai1 senses the amount of cholesterol in the plasma membrane and apparently the interaction of Orai1 with cholesterol inhibits its activity, thereby limiting store-operated calcium entry [1]. High affinity Ca²⁺ binding to the pore entrance of Orai channels creates a local extracellular calcium accumulating region CAR and provides fundamental insight into the unique mechanism of Ca²⁺ permeation of Orai channels [2]. The combination of computational modeling of Orai channels and molecular dynamics simulations provided by the team in Nove Hrady, and functional patch clamp, site-directed mutagenesis and experimental biophysical experiments performed by the Linz Team allows to propose that the Orai1 channel architecture with a close proximity of CAR to the selectivity filter, which enables Ca²⁺-selective ion permeation, enhances the local extracellular Ca²⁺ concentration to maintain Ca²⁺-dependent gene regulation even in environments with relatively low Ca²⁺concentrations [2].

 

1.         Isabella Derler, Isaac Jardin, Peter B Stathopulos, Martin Muik, Marc Fahrner, Vaselina Zayats, Saurabh Pandey, Michael Poteser, Barbara Lackner, Marketa Absolonova, Klaus Groschner, Rüdiger Ettrich, Mitsu Ikura, Christoph Romanin (2016) Cholesterol binding modulates Orai1 channel function Science Signaling 9 (412): ra10. Jan 26.

 

2.         Irene Frischauf, Vasilina Zayats, Michael Deix, Anna Hochreiter, Isaac Jardin Polo, Martin Muik, Barbara Lackner, Barbora Svobodova, Teresa Pammer, Monika Litvinukova, Amrutha Arumbakam Sridhar, Isabella Derler, Ivan Bogeski, Christoph Romanin, Rüdiger Ettrich, Rainer Schindl (2015) A calcium accumulating region, CAR, in the Orai1 channel enhances Ca2+- permeation and SOCE-induced gene transcription Science Signaling 8 (408): ra131. Dec 22.