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

Megumi Yamashita; Priscilla S.W. Yeung; Christopher E. Ing; Beth A. McNally; Régis Pomès; Murali Prakriya

doi:10.1038/ncomms14512

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

Megumi Yamashita, Priscilla S.W. Yeung, Christopher E. Ing, Beth A. McNally, Régis Pomès, Murali Prakriya^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

80 Scopus citations

Abstract

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.

Original language	English (US)
Article number	14512
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14512
State	Published - Feb 21 2017

Funding

This work was supported by NIH Grants NS057499 and GM114210 (to M.P.) and Canadian Institutes of Health Research grant MOP-130461 (to R.P). P.S.-W.Y. was supported by an NIH predoctoral training fellowship 5T32GM008382 and the Medical Scientist Training Program. Northwestern University's Center for Advanced Microscopy is supported by NCRR 1S10 RR031680-01.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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title = "STIM1 activates CRAC channels through rotation of the pore helix to open a hydrophobic gate",

abstract = "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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AU - Ing, Christopher E.

AU - McNally, Beth A.

AU - Pomès, Régis

AU - Prakriya, Murali

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N2 - 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.

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

Abstract

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