Abstract
The calcium release-activated calcium channel, composed of the Orai channel and the STIM protein, plays a crucial role in maintaining the Ca2+ concentration in cells. Previous studies showed that the L138F mutation in the human Orai1 creates a constitutively open channel independent of STIM, causing severe myopathy, but how the L138F mutation activates Orai1 is still unclear. Here, based on the crystal structure of Drosophila melanogaster Orai (dOrai), molecular dynamics simulations for the wild-type (WT) and the L210F (corresponding to L138F in the human Orai1) mutant were conducted to investigate their structural and dynamical properties. The results showed that the L210F dOrai mutant tends to have a more hydrated hydrophobic region (V174 to F171), as well as more dilated basic region (K163 to R155) and selectivity filter (E178). Sodium ions were located deeper in the mutant than in the wild-type. Further analysis revealed two local but essential conformational changes that may be the key to the activation. A rotation of F210, a previously unobserved feature, was found to result in the opening of the K163 gate through hydrophobic interactions. At the same time, a counter-clockwise rotation of F171 occurred more frequently in the mutant, resulting in a wider hydrophobic gate with more hydration. Ultimately, the opening of the two gates may facilitate the opening of the Orai channel independent of STIM.
Highlights
Calcium ions, as an essential second messenger in cells, regulate a wide range of physiological processes
The results showed that the systems reached equilibrium states at about 300 ns (Figures 2A,B) with the Cα-root mean square deviation (RMSD) of the WT and the mutant converging to 0.41 and 0.47 nm respectively
Our results were more comparable to the work of Dong et al (Dong et al, 2013) owing to similar simulation setups, indicating that the stability of Orai can be influenced by the surrounding environment
Summary
As an essential second messenger in cells, regulate a wide range of physiological processes. Store-operated calcium entry (SOCE) was identified to explain how depletion of endoplasmic reticulum (ER) Ca2+ stores evokes Ca2+ influx across the plasma membrane. (Engh et al, 2012; Feske et al, 2012; Soboloff et al, 2012; Prakriya and Lewis, 2015) Both loss-offunction and gain-of-function mutations of the CRAC channel lead to devastating immunodeficiencies, bleeding disorders and muscle weakness. The STIMs are single-pass ER transmembrane proteins, function as the sensor of the Ca2+ concentration inside the ER, bind to and activate Orai channels. STIM1 and STIM2, are included in the STIMs family and the former one is more widely studied. The calcium channel that opens to permit the influx of the calcium ions, locates on the plasma membrane and contains three closely conserved mammalian homologs, Orai, Orai and Orai. The calcium channel that opens to permit the influx of the calcium ions, locates on the plasma membrane and contains three closely conserved mammalian homologs, Orai, Orai and Orai3. (Vig et al, 2006; Hoth et al, 2013)
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