Sequential Steps of CRAC Channel Activation

Palty, Raz; Fu, Zhu; Isacoff, Ehud Y.

doi:10.1016/j.celrep.2017.05.025

Cited by 28 publications

(20 citation statements)

References 59 publications

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“…; Palty et al . ). This motion presumably necessitates flexibility of the 263 SHK 265 domain because mutations that are predicted to alter the orientation of the bend (e.g.…”

Section: How Does Stim1 Binding Activate Orai1?mentioning

confidence: 97%

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Molecular basis of allosteric Orai1 channel activation by STIM1

Yeung

Yamashita

Prakriya

2019

The Journal of Physiology

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Store-operated Ca 2+ entry through Orai1 channels is a primary mechanism for Ca 2+ entry in many cells and mediates numerous cellular effector functions ranging from gene transcription to exocytosis. Orai1 channels are amongst the most Ca 2+ -selective channels known and are activated by direct physical interactions with the endoplasmic reticulum Ca 2+ sensor stromal interaction molecule 1 (STIM1) in response to store depletion triggered by stimulation of a variety of cell surface G-protein coupled and tyrosine kinase receptors. Work in the last decade has revealed that the Orai1 gating process is highly cooperative and strongly allosteric, likely driven by a wave of interdependent conformational changes throughout the protein originating in the peripheral C-terminal ligand binding site and culminating in pore opening. In this review, we survey the structural and molecular features in Orai1 that contribute to channel gating and consider how they give rise to the unique biophysical fingerprint of Orai1 currents.

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“…; Palty et al . ). This motion presumably necessitates flexibility of the 263 SHK 265 domain because mutations that are predicted to alter the orientation of the bend (e.g.…”

Section: How Does Stim1 Binding Activate Orai1?mentioning

confidence: 97%

“…This finding suggests that the mutations stabilize Orai1 channels in partially open, intermediate states along the STIM1 gating pathway (Palty et al . ; Yeung et al . ).…”

Section: How Does Stim1 Binding Activate Orai1?mentioning

confidence: 99%

Molecular basis of allosteric Orai1 channel activation by STIM1

Yeung

Yamashita

Prakriya

2019

The Journal of Physiology

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“…local conformational changes at the agonist binding site (16,20,21) are allosterically relayed to the distally located channel gate in the pore (8,11) through an unknown pathway.…”

Section: Significancementioning

confidence: 99%

Mapping the functional anatomy of Orai1 transmembrane domains for CRAC channel gating

Yeung

Yamashita

Ing

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

199

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Store-operated Orai1 channels are activated through a unique inside-out mechanism involving binding of the endoplasmic reticulum Ca sensor STIM1 to cytoplasmic sites on Orai1. Although atomic-level details of Orai structure, including the pore and putative ligand binding domains, are resolved, how the gating signal is communicated to the pore and opens the gate is unknown. To address this issue, we used scanning mutagenesis to identify 15 residues in transmembrane domains (TMs) 1-4 whose perturbation activates Orai1 channels independently of STIM1. Cysteine accessibility analysis and molecular-dynamics simulations indicated that constitutive activation of the most robust variant, H134S, arises from a pore conformational change that opens a hydrophobic gate to augment pore hydration, similar to gating evoked by STIM1. Mutational analysis of this locus suggests that H134 acts as steric brake to stabilize the closed state of the channel. In addition, atomic packing analysis revealed distinct functional contacts between the TM1 pore helix and the surrounding TM2/3 helices, including one set mediated by a cluster of interdigitating hydrophobic residues and another by alternative ridges of polar and hydrophobic residues. Perturbing these contacts via mutagenesis destabilizes STIM1-mediated Orai1 channel gating, indicating that these bridges between TM1 and the surrounding TM2/3 ring are critical for conveying the gating signal to the pore. These findings help develop a framework for understanding the global conformational changes and allosteric interactions between topologically distinct domains that are essential for activation of Orai1 channels.

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“…These include the identification of the part of the STIM1 molecule that interacts with the Orai1 channel (called SOAR, Yuan et al 2009, or CAD, Park et al 2009) and the characterization of an intramolecular interaction between the SOAR domain and the first membrane-adjacent coiled-coil domain of the cytoplasmic part of STIM1 that keeps the SOAR domain from activating Orai1 in the resting state (Muik et al 2011;Zhou et al 2013;Fahrner et al 2014;Ma et al 2015). Similar structural and mutational studies reveal the key interactive motifs that form the basis of interaction between SOAR and Orai1 and the mechanism of Orai1 channel activation (Derler et al 2013;Gudlur et al 2014;Zhou et al 2016;Nwokonko et al 2017;Palty et al 2017).…”

Section: Stim and Orai Proteins Constitute Store-operated Ca 2+ Entrymentioning

confidence: 99%

Ca²⁺ and lipid signals hold hands at endoplasmic reticulum–plasma membrane contact sites

Balla

2018

The Journal of Physiology

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Discovery of the STIM1 and Orai proteins as the principal components of store-operated Ca entry has drawn attention to contact sites between the endoplasmic reticulum (ER) and the plasma membrane (PM). Such contacts between adjacent membranes of different cellular organelles, primarily between the mitochondria and the ER, had already been known as the sites where Ca released from the ER can be efficiently channelled to the mitochondria and also where phosphatidylserine synthesis and transfer takes place. Recent studies have identified contact sites between virtually every organelle and the ER and the functional importance of these small specialized membrane domains is increasingly recognized. Most recent developments have highlighted the role of phosphatidylinositol 4-phosphate gradients as critical determinants of the non-vesicular transport of various lipids from the ER to other organelles such as the Golgi or PM. As we learn more about membrane contact sites it becomes apparent that Ca is not only transported at these sites but also controls both the dynamics and the lipid transfer efficiency of these processes. Conversely, lipids are critical for regulating the Ca entry process. This review will summarize some of the most exciting recent developments in this rapidly expanding research field.

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Sequential Steps of CRAC Channel Activation

Cited by 28 publications

References 59 publications

Molecular basis of allosteric Orai1 channel activation by STIM1

Molecular basis of allosteric Orai1 channel activation by STIM1

Mapping the functional anatomy of Orai1 transmembrane domains for CRAC channel gating

Ca²⁺ and lipid signals hold hands at endoplasmic reticulum–plasma membrane contact sites

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Sequential Steps of CRAC Channel Activation

Cited by 28 publications

References 59 publications

Molecular basis of allosteric Orai1 channel activation by STIM1

Molecular basis of allosteric Orai1 channel activation by STIM1

Mapping the functional anatomy of Orai1 transmembrane domains for CRAC channel gating

Ca2+ and lipid signals hold hands at endoplasmic reticulum–plasma membrane contact sites

Contact Info

Product

Resources

About

Ca²⁺ and lipid signals hold hands at endoplasmic reticulum–plasma membrane contact sites