| Autor: |
Yamashita M; Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA., Yeung PS; Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA., Ing CE; Molecular Structure and Function, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 0A4.; Department of Biochemistry, University of Toronto, 101 College Street, Toronto, Ontario, Canada M5G IL7., McNally BA; Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA., Pomès R; Molecular Structure and Function, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 0A4.; Department of Biochemistry, University of Toronto, 101 College Street, Toronto, Ontario, Canada M5G IL7., Prakriya M; Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. |
| Abstrakt: |
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. |
