Molecular anatomy of the early events in STIM1 activation – oligomerization or conformational change?

Korzeniowski, Marek; Wisniewski, Éva; Baird, Barbara; Holowka, David; Balla, Tamás

doi:10.1242/jcs.205583

Cited by 20 publications

(17 citation statements)

References 35 publications

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“…In the Ca 2+ -bound state, the luminal EF-SAM regions in the dimer are held apart; these domains are critical for preventing spontaneous activation of STIM1 (Li et al 2007;Korzeniowski et al 2017). This configuration allows the cytosolic CC1 domain to associate with CAD/SOAR to sequester it near the ER membrane (Fig.…”

Section: Activation Of Stim By Store Depletionmentioning

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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Section: Activation Of Stim By Store Depletionmentioning

confidence: 99%

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

Lewis

2019

Cold Spring Harb Perspect Biol

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“…; Korzeniowski et al . ). The two fragments were closely associated in resting cells, as judged by FRET between the fluorescently labelled STIM fragments or by SOAR/CAD localization to the ER, but came apart upon store depletion.…”

Section: Introductionmentioning

confidence: 97%

STIM calcium sensing and conformational change

Gudlur

Zeraik

Hirve

et al. 2019

The Journal of Physiology

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The control of calcium influx at the plasma membrane by endoplasmic reticulum (ER) calcium stores, a process common to invertebrates and vertebrates, is central to physiological calcium signalling and cellular calcium balance. Stromal interaction molecule 1 (STIM1) is a calcium sensor and regulatory protein localized to the ER. ORAI1 is a calcium channel in the plasma membrane (PM). In outline, STIM1 senses an ER-luminal calcium decrease, relocalizes to ER-PM junctions, and recruits and gates ORAI1 channels. Recent work, reviewed here, has offered detailed insight into the process of sensing and communicating ER calcium-store depletion, and particularly into the STIM1 conformational change that is the basis for communication between the ER and the PM.Abstract figure legend A shift in perspective on stromal interaction molecule (STIM) calcium sensing and the mechanism of STIM activation. The endoplasmic reticulum (ER)-luminal domains of the calcium sensors STIM1 and STIM2 bind multiple calcium ions per monomer in the resting state, and the cytoplasmic domains are folded back near the ER membrane. STIM proteins are activated when all bound calcium ions dissociate. This results in luminal domain dimerization and a concerted conformational change that triggers release of the resting CC1-SOAR/CAD interaction and extension of the STIM cytoplasmic domain. This model revises earlier proposed mechanisms of STIM activation that were centred around a single calcium-binding site per monomer and activation driven by unfolding and oligomerization of STIM ER-luminal domains.

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“…The SOAR/CAD domain is folded back against CC1 in a way that precludes its effective interaction with plasma membrane ORAI channels 19 , 20 . STIM1 activation is triggered when Ca 2+ dissociates from STIM1 ER-luminal domains, the EFSAM domains rearrange or dimerize, and the STIM1 cytoplasmic domains undergo a conformational change that releases the SOAR/CAD domains and the polybasic tails 8 , 19 , 21 – 27 . Biochemical and biophysical studies have established that STIM communicates the store-depletion signal to the cytoplasm via STIM–STIM association in the transmembrane and predicted coiled coil 1 (CC1) regions 19 , 26 – 28 .…”

Section: Introductionmentioning

confidence: 99%

Calcium sensing by the STIM1 ER-luminal domain

et al. 2018

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Stromal interaction molecule 1 (STIM1) monitors ER-luminal Ca2+ levels to maintain cellular Ca2+ balance and to support Ca2+ signalling. The prevailing view has been that STIM1 senses reduced ER Ca2+ through dissociation of bound Ca2+ from a single EF-hand site, which triggers a dramatic loss of secondary structure and dimerization of the STIM1 luminal domain. Here we find that the STIM1 luminal domain has 5–6 Ca2+-binding sites, that binding at these sites is energetically coupled to binding at the EF-hand site, and that Ca2+ dissociation controls a switch to a second structured conformation of the luminal domain rather than protein unfolding. Importantly, the other luminal-domain Ca2+-binding sites interact with the EF-hand site to control physiological activation of STIM1 in cells. These findings fundamentally revise our understanding of physiological Ca2+ sensing by STIM1, and highlight molecular mechanisms that govern the Ca2+ threshold for activation and the steep Ca2+ concentration dependence.

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Molecular anatomy of the early events in STIM1 activation – oligomerization or conformational change?

Cited by 20 publications

References 35 publications

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

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

STIM calcium sensing and conformational change

Calcium sensing by the STIM1 ER-luminal domain

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