STIM1 activates CRAC channels through rotation of the pore helix to open a hydrophobic gate

• Published in: Nature communications Vol. 8; no. 1; pp. 14512 - 13
• Main Authors: Yamashita, Megumi, Yeung, Priscilla S.-W., Ing, Christopher E., McNally, Beth A., Pomès, Régis, Prakriya, Murali
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.02.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 14/63; 38/70; 631/45/269/1146; 631/57/2270/1140; 9/74; Amino acids; Calcium - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Hydration; Hydrophobic and Hydrophilic Interactions; Ion Channel Gating; Ions; Microscopy, Confocal; Models, Molecular; multidisciplinary; Mutation; Neoplasm Proteins - chemistry; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; ORAI1 Protein - chemistry; ORAI1 Protein - genetics; ORAI1 Protein - metabolism; Pharmacology; Phenylalanine - chemistry; Phenylalanine - genetics; Phenylalanine - metabolism; Protein Structure, Secondary; Rotation; Science; Science (multidisciplinary); Simulation; Stromal Interaction Molecule 1 - chemistry; Stromal Interaction Molecule 1 - genetics; Stromal Interaction Molecule 1 - metabolism; Valine - chemistry; Valine - genetics; Valine - metabolism; Toronto Ontario Canada; Canada
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14512

Store-operated Ca 2+ release-activated Ca 2+ (CRAC) channels constitute a major pathway for Ca 2+ influx and mediate many essential signalling functions in animal cells, yet how they open remains elusive. Here, we investigate the gating mechanism of the human CRAC channel Orai1 by its activator, stromal interacting molecule 1 (STIM1). We find that two rings of pore-lining residues, V102 and F99, work together to form a hydrophobic gate. Mutations of these residues to polar amino acids produce channels with leaky gates that conduct ions in the resting state. STIM1-mediated channel activation occurs through rotation of the pore helix, which displaces the F99 residues away from the pore axis to increase pore hydration, allowing ions to flow through the V102-F99 hydrophobic band. Pore helix rotation by STIM1 also explains the dynamic coupling between CRAC channel gating and ion selectivity. This hydrophobic gating mechanism has implications for CRAC channel function, pharmacology and disease-causing mutations. Store-operated Ca 2+ channels (CRAC) are involved in several cellular functions. Here the authors identify a hydrophobic gate in the CRAC pore and show that CRAC activation by STIM1 involves rotation of the pore helix that hydrates this region to allow ion passage through the pore.