TY - JOUR TI - A sulfur-aromatic gate latch is essential for opening of the Orai1 channel pore AU - Yeung, Priscilla S-W AU - Ing, Christopher E AU - Yamashita, Megumi AU - Pomès, Régis AU - Prakriya, Murali A2 - Lewis, Richard S A2 - Swartz, Kenton J A2 - Lewis, Richard S A2 - Cahalan, Michael D VL - 9 PY - 2020 DA - 2020/10/30 SP - e60751 C1 - eLife 2020;9:e60751 DO - 10.7554/eLife.60751 UR - https://doi.org/10.7554/eLife.60751 AB - Sulfur-aromatic interactions occur in the majority of protein structures, yet little is known about their functional roles in ion channels. Here, we describe a novel molecular motif, the M101 gate latch, which is essential for gating of human Orai1 channels via its sulfur-aromatic interactions with the F99 hydrophobic gate. Molecular dynamics simulations of different Orai variants reveal that the gate latch is mostly engaged in open but not closed channels. In experimental studies, we use metal-ion bridges to show that promoting an M101-F99 bond directly activates Orai1, whereas disrupting this interaction triggers channel closure. Mutational analysis demonstrates that the methionine residue at this position has a unique combination of length, flexibility, and chemistry to act as an effective latch for the phenylalanine gate. Because sulfur-aromatic interactions provide additional stabilization compared to purely hydrophobic interactions, we infer that the six M101-F99 pairs in the hexameric channel provide a substantial energetic contribution to Orai1 activation. KW - CRAC channels KW - orai1 KW - STIM1 KW - store-operated calcium entry KW - ion channel gating KW - sulfur-aromatic interaction JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -