Distinct gating mechanism of SOC channel involving STIM–Orai coupling and an intramolecular interaction of Orai in
            <i>Caenorhabditis elegans</i>

Kim, Kyu Min; Wijerathne, Tharaka D.; Hur, Jin‐Hoe; Kang, Uk Jung; Kim, Ihn Hyeong; Kweon, Yeong Cheon; Lee, Ah Reum; Jeong, Su Ji; Lee, Sang Kwon; Lee, Yoon Young; Sim, Bo-Woong; Lee, Jonghee; Baig, Chunggi; Kim, Sun-Uk; Chang, Kyu‐Tae; Lee, Kyu Pil; Park, Chan Young

doi:10.1073/pnas.1714986115

Cited by 13 publications

(14 citation statements)

References 48 publications

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“…postulated that in the context of Orai in Caenorhabditis elegans , the N‐ and C‐terminal tails, which are bound to the TM2–3 loop at rest, are displaced during STIM1 binding (Kim et al . ). They proposed that this unbinding step between the TM2–3 loop and the N‐ and C‐termini permits channel opening (Kim et al .…”

Section: How Does Stim1 Binding Activate Orai1?mentioning

confidence: 97%

“…They proposed that this unbinding step between the TM2–3 loop and the N‐ and C‐termini permits channel opening (Kim et al . ). Taken together, both studies imply that an interaction between the N‐terminus and the TM2–3 loop favours the closed state whereas release of this interaction biases the channel towards an open configuration.…”

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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Section: How Does Stim1 Binding Activate Orai1?mentioning

confidence: 97%

Section: How Does Stim1 Binding Activate Orai1?mentioning

confidence: 97%

Molecular basis of allosteric Orai1 channel activation by STIM1

Yeung

Yamashita

Prakriya

2019

The Journal of Physiology

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“…Very recently, a published X-ray crystal structure of the H206A mutant of dOrai at 6.7 Å resolution shows pore widening and a significant conformational change of the TM4-ext, although rotation of the TM helices is not evident (Hou et al., 2018). In addition, in Orai from Caenorhabditis elegans , the intracellular loop was found to be involved in gating, which was not proposed for mammalian Orai (Kim et al., 2018). Gating of the channel was also affected by some cofactors such as lipid composition.…”

Section: Introductionmentioning

confidence: 93%

Toward a Model for Activation of Orai Channel

et al. 2019

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Store-operated calcium release-activated calcium (CRAC) channels mediate a variety of cellular signaling functions. The CRAC channel pore-forming protein, Orai1, is a hexamer arranged with 3-fold symmetry. Despite its importance in moving Ca 2+ ions into cells, a detailed mechanistic understanding of Orai1 activation is lacking. Herein, a working model is proposed for the putative open state of Orai from Drosophila melanogaster (dOrai), which involves a ''twist-to-open'' gating mechanism. The proposed model is supported by energetic, structural, and experimental evidence. Fluorescent imaging demonstrates that each subunit on the intracellular side of the pore is inherently strongly cross-linked, which is important for coupling to STIM1, the pore activator, and graded activation of the Orai1 channel. The proposed model thus paves the way for understanding key aspects of calcium signaling at a molecular level.

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“…Binding of STIM to the C-terminus of Orai (the cytosolic extension of the M4 helix, or M4ext) is well established, based on findings that mutagenesis or deletion of the M4ext inhibits Orail activation and clustering at ER-PM junctions as well as binding of CAD/SOAR to Orail C-terminal fragments (for review, see Prakriya and Lewis 2015). Studies of human Orail found no evidence for binding to the 2-3 loop, but this occurs in C. elegans, suggesting a different mode of activation in this species (Kim et al 2018).…”

Section: How Stim Binds To Oraimentioning

confidence: 99%

Store-Operated Calcium Channels: From Function to Structure and Back Again

Lewis

2019

Cold Spring Harb Perspect Biol

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Store-operated calcium (Ca 2+) entry (SOCE) occurs through a widely distributed family of ion channels activated by the loss of Ca 2+ from the endoplasmic reticulum (ER). The best understood of these is the Ca 2+ release-activated Ca 2+ (CRAC) channel, which is notable for its unique activation mechanism as well as its many essential physiological functions and the diverse pathologies that result from dysregulation. In response to ER Ca 2+ depletion, CRAC channels are formed through a diffusion trap mechanism at ER-plasma membrane (PM) junctions, where the ER Ca 2+ sensing stromal interaction molecule (STIM) proteins bind and activate hexamers of Orai pore-forming proteins to trigger Ca 2+ entry. Cell biological studies are clarifying the architecture of ER-PM junctions, their roles in Ca 2+ and lipid transport, and functional interactions with cytoskeletal proteins. Key structural studies of STIM and Orai have inspired mutagenesis and electrophysiological approaches that now suggest novel mechanisms that control toggling of STIM between inactive and active states, models for STIM-Orai binding and channel gating, and how STIM binding to all six Orai channel subunits triggers opening while establishing signature CRAC channel characteristics including extremely high Ca 2+ selectivity and low Ca 2+ conductance. OVERVIEW OF STORE-OPERATED CALCIUM ENTRY One of the major pathways for Ca 2+ influx across the plasma membrane (PM) of cells is store-operated Ca 2+ entry (SOCE), so called because it is triggered by stimuli that reduce the level of Ca 2+ in the endoplasmic reticulum (ER); aka the major cellular "Ca 2+ store") (Putney 1986). Initially described in electrically non-excitable cells, SOCE is now known to operate in practically all cells, including excitable cells such as neurons and muscle. At a cellular level, SOCE controls a wide variety of processes, including gene expression, secretion, motility, and maintaining a high Ca 2+ concentration in the ER. Its physiological importance is underscored by numerous pathologies caused by gain or loss of function. In humans, loss of function leads to severe combined immunodeficiency (SCID), autoimmunity, myopathy, and ectodermal dysplasia, while gain of function causes York and Stormorken syndromes (characterized by thrombocytopenia, bleeding diathesis, miosis, and tubular aggregate myopathy) (Lacruz and Feske 2015). The dire consequences of dysregulation demonstrate the importance of precisely controlling SOCE to drive a variety of essential physiological functions.

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Distinct gating mechanism of SOC channel involving STIM–Orai coupling and an intramolecular interaction of Orai in Caenorhabditis elegans

Cited by 13 publications

References 48 publications

Molecular basis of allosteric Orai1 channel activation by STIM1

Molecular basis of allosteric Orai1 channel activation by STIM1

Toward a Model for Activation of Orai Channel

Store-Operated Calcium Channels: From Function to Structure and Back Again

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