Structural determinants of ion permeation in CRAC channels

Beth A. McNally, Megumi Yamashita, Anita Engh, Murali Prakriya*

*Corresponding author for this work

Research output: Contribution to journalArticle

115 Scopus citations

Abstract

CRAC channels generate Ca2+ signals critical for the activation of immune cells and exhibit an intriguing pore profile distinguished by extremely high Ca2+ selectivity, low Cs+ permeability, and small unitary conductance. To identify the ion conduction pathway and gain insight into the structural bases of these permeation characteristics, we introduced cysteine residues in the CRAC channel pore subunit, Orai1, and probed their accessibility to various thiolreactive reagents. Our results indicate that the architecture of the ion conduction pathway is characterized by a flexible outer vestibule formed by the TM1-TM2 loop, which leads to a narrow pore flanked by residues of a helical TM1 segment. Residues in TM3, and specifically, E190, a residue considered important for ion selectivity, are not close to the pore. Moreover, the outer vestibule does not significantly contribute to ion selectivity, implying that Ca2+ selectivity is conferred mainly by E106. The ion conduction pathway is sufficiently narrow along much of its length to permit stable coordination of Cd2+ by several TM1 residues, which likely explains the slow flux of ions within the restrained geometry of the pore. These results provide a structural framework to understand the unique permeation properties of CRAC channels.

Original languageEnglish (US)
Pages (from-to)22516-22521
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number52
DOIs
StatePublished - Dec 19 2009

Keywords

  • Orai1
  • STIM1
  • Store-operated channels

ASJC Scopus subject areas

  • General

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