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

被引：0
作者：
Megumi Yamashita
Priscilla S.-W. Yeung
Christopher E. Ing
Beth A. McNally
Régis Pomès
Murali Prakriya
机构：
[1] Feinberg School of Medicine,Department of Pharmacology
[2] Northwestern University,Department of Biochemistry
[3] Molecular Structure and Function,undefined
[4] Hospital for Sick Children,undefined
[5] University of Toronto,undefined
[6] University of Toronto,undefined
来源：
Nature Communications | / 8卷
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摘要：
Store-operated Ca2+ release-activated Ca2+ (CRAC) channels constitute a major pathway for Ca2+ 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.
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