Location and Function of STIM1 in the Activation of Ca2+ Entry Signals (original) (raw)
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STIM proteins: dynamic calcium signal transducers
Nature Reviews Molecular Cell Biology, 2012
Stromal interaction molecule (STIM) proteins function in cells as dynamic coordinators of cellular calcium (Ca 2+) signals. Spanning the endoplasmic reticulum (ER) membrane, they sense tiny changes in the levels of Ca 2+ stored within the ER lumen. As ER Ca 2+ is released to generate primary Ca 2+ signals, STIM proteins undergo an intricate activation reaction and rapidly translocate into junctions formed between the ER and the plasma membrane. There, STIM proteins tether and activate the highly Ca 2+-selective Orai channels to mediate finely controlled Ca 2+ signals and to homeostatically balance cellular Ca 2+. Details are emerging on the remarkable organization within these STIM-induced junctional microdomains and the identification of new regulators and alternative target proteins for STIM. Calcium (Ca 2+) signals are crucial for the control a broad range of cellular functions, including secretion, excitation, contraction, motility, metabolism, transcription, growth, cell division and apoptosis. The numerous pumps and channels that comprise the machinery for generating cellular Ca 2+ signals are functionally well defined. However, less understood are the mechanisms that coordinate the operation of this machinery to generate the temporally and spatially precise Ca 2+ signals that selectively control individual cell functions. Ca 2+ signalling involves the concerted action of Ca 2+ release channels in Ca 2+ storage organelles and Ca 2+ entry channels in the plasma membrane (BOX 1). The recently identified stromal interaction molecule (STIM) proteins 1,2 , STIM1 and STIM2, are crucial in coordinating Ca 2+ release and entry signals and in maintaining cellular Ca 2+ homeostasis. Box 1 Principles of Ca 2+ signalling The events that maintain cellular Ca 2+ signalling during homeostasis are shown in part a of the figure. Resting cells (left) maintain cytosolic Ca 2+ in the nM range through sarcoplasmic reticulum Ca 2+ ATPase (SERCA) and plasma membrane Ca 2+ ATPase (PMCA) pumps. Following ligand binding to phospholipase C (PLC)-coupled receptors (right), the second messengers inositol-1,4,5-trisphosphate (Ins(1,4,5) P 3) and diacylglycerol (DAG) are generated through breakdown of phosphatidylinositol-4,5
STIM1 has a plasma membrane role in the activation of store-operated Ca2+ channels
Proceedings of the National Academy of Sciences, 2006
Receptor-induced Ca 2؉ signals are key to the function of all cells and involve release of Ca 2؉ from endoplasmic reticulum (ER) stores, triggering Ca 2؉ entry through plasma membrane (PM) ''storeoperated channels'' (SOCs). The identity of SOCs and their coupling to store depletion remain molecular and mechanistic mysteries. The single transmembrane-spanning Ca 2؉ -binding protein, STIM1, is necessary in this coupling process and is proposed to function as an ER Ca 2؉ sensor to provide the trigger for SOC activation. Here we reveal that, in addition to being an ER Ca 2؉ sensor, STIM1 functions within the PM to control operation of the Ca 2؉ entry channel itself. Increased expression levels of STIM1 correlate with a gain in function of Ca 2؉ release-activated Ca 2؉ (CRAC) channel activity. Point mutation of the N-terminal EF hand transforms the CRAC channel current (I CRAC) into a constitutively active, Ca 2؉ store-independent mode. Mutants in the EF hand and cytoplasmic C terminus of STIM1 alter operational parameters of CRAC channels, including pharmacological profile and inactivation properties.
STIM2 Is an Inhibitor of STIM1-Mediated Store-Operated Ca 2+ Entry
Current Biology, 2006
The coupling mechanism between endoplasmic reticulum (ER) Ca 2+ stores and plasma membrane (PM) storeoperated channels (SOCs) remains elusive . STIM1 was shown to play a crucial role in this coupling process ; however, the role of the closely related STIM2 protein remains undetermined. We reveal that STIM2 is a powerful SOC inhibitor when expressed in HEK293, PC12, A7r5, and Jurkat T cells. This contrasts with gain of SOC function in STIM1-expressing cells. While STIM1 is expressed in both the ER and plasma membrane, STIM2 is expressed only intracellularly. Store depletion induces redistribution of STIM1 into distinct ''puncta.'' STIM2 translocates into puncta upon store depletion only when coexpressed with STIM1. Double labeling shows coincidence of STIM1 and STIM2 within puncta, and immunoprecipitation reveals direct interactions between STIM1 and STIM2. Independent of store depletion, STIM2 colocalizes with and blocks the function of a STIM1 EF-hand mutant that preexists in puncta and is constitutively coupled to activate SOCs. Thus, whereas STIM1 is a required mediator of SOC activation, STIM2 is a powerful inhibitor of this process, interfering with STIM1-mediated SOC activation at a point downstream of puncta formation. The opposing functions of STIM1 and STIM2 suggest they may play a coordinated role in controlling SOC-mediated Ca 2+ entry signals.
Molecular Determinants for STIM1 Activation During Store- Operated Ca2+ Entry
Current Molecular Medicine, 2017
Background-STIM/ORAI-mediated store-operated Ca 2+ entry (SOCE) mediates a myriad of Ca 2+-dependent cellular activities in mammals. Genetic defects in STIM1/ORAI1 lead to devastating severe combined immunodeficiency; whereas gain-of-function mutations in STIM1/ ORAI1 are intimately associated with tubular aggregate myopathy. At molecular level, a decrease in the Ca 2+ concentrations within the lumen of endoplasmic reticulum (ER) initiates multimerization of the STIM1 luminal domain to switch on the STIM1 cytoplasmic domain to engage and gate ORAI channels, thereby leading to the ultimate Ca 2+ influx from the extracellular space into the cytosol. Despite tremendous progress made in dissecting functional STIM1-ORAI1 coupling, the activation mechanism of SOCE remains to be fully characterized. Objective and Methods-Building upon a robust fluorescence resonance energy transfer assay designed to monitor STIM1 intramolecular autoinhibition, we aimed to systematically dissect the molecular determinants required for the activation and oligomerization of STIM1. Results-Here we showed that truncation of the STIM1 luminal domain predisposes STIM1 to adopt a more active conformation. Replacement of the single transmembrane (TM) domain of
STIM1 regulates store-operated Ca2+ entry in oocytes
Developmental Biology, 2009
The single transmembrane-spanning Ca 2+-binding protein, STIM1, has been proposed to function as a Ca 2+ sensor that links the endoplasmic reticulum to the activation of store-operated Ca 2+ channels. In this study, the presence, subcellular localization and function of STIM1 in store-operated Ca 2+ entry in oocytes was investigated using the pig as a model. Cloning and sequence analysis revealed the presence of porcine STIM1 with a coding sequence of 2058 bp. In oocytes with full cytoplasmic Ca 2+ stores, STIM1 was localized predominantly in the inner cytoplasm as indicated by immunocytochemistry or overexpression of human STIM1 conjugated to the yellow fluorescent protein. Depletion of the Ca 2+ stores was associated with redistribution of STIM1 along the plasma membrane. Increasing STIM1 expression resulted in enhanced Ca 2+ influx after store depletion and subsequent Ca 2+ add-back; the influx was inhibited when the oocytes were pretreated with lanthanum, a specific inhibitor of store-operated Ca 2+ channels. When STIM1 expression was suppressed using siRNAs, there was no change in cytosolic free Ca 2+ levels in the store-depleted oocytes after Ca 2+ add-back. The findings suggest that in oocytes, STIM1 serves as a sensor of Ca 2+ store content that after store depletion moves to the plasma membrane to stimulate store-operated Ca 2+ entry. Published by Elsevier Inc.
Signal transduction: STIM1 senses both Ca2+ and heat
Nature Chemical Biology, 2011
STIM proteins are ubiquitous endoplasmic reticulum Ca 2+ sensors that rapidly translocate to couple with 'store-operated' Orai Ca 2+ channels when luminal Ca 2+ levels are low. STIM1 also senses heat changes, which trigger a similar translocation and prime STIM1 to activate Orai, suggesting that STIM1 functions as a sensor of multiple stress signals.
Novel Role for STIM1 as a Trigger for Calcium Influx Factor Production
Journal of Biological Chemistry, 2008
STIM1 has been recently identified as a Ca 2؉ sensor in endoplasmic reticulum (ER) and an initiator of the store-operated Ca 2؉ entry (SOCE) pathway, but the mechanism of SOCE activation remains controversial. Here we focus on the early ERdelimited steps of the SOCE pathway and demonstrate that STIM1 is critically involved in initiating of production of calcium influx factor (CIF), a diffusible messenger that can deliver the signal from the stores to plasma membrane and activate SOCE. We discovered that CIF production is tightly coupled with STIM1 expression and requires functional integrity of its intraluminal sterile ␣-motif (SAM) domain. We demonstrate that 1) molecular knockdown or overexpression
Inside-out Ca2+ signalling prompted by STIM1 conformational switch
Nature Communications, 2015
Store-operated Ca 2 þ entry mediated by STIM1 and ORAI1 constitutes one of the major Ca 2 þ entry routes in mammalian cells. The molecular choreography of STIM1-ORAI1 coupling is initiated by endoplasmic reticulum (ER) Ca 2 þ store depletion with subsequent oligomerization of the STIM1 ER-luminal domain, followed by its redistribution towards the plasma membrane to gate ORAI1 channels. The mechanistic underpinnings of this inside-out Ca 2 þ signalling were largely undefined. By taking advantage of a unique gain-of-function mutation within the STIM1 transmembrane domain (STIM1-TM), here we show that local rearrangement, rather than alteration in the oligomeric state of STIM1-TM, prompts conformational changes in the cytosolic juxtamembrane coiled-coil region. Importantly, we further identify critical residues within the cytoplasmic domain of STIM1 (STIM1-CT) that entail autoinhibition. On the basis of these findings, we propose a model in which STIM1-TM reorganization switches STIM1-CT into an extended conformation, thereby projecting the ORAI-activating domain to gate ORAI1 channels.
The Journal of physiology, 2007
Recent studies have indicated a critical role for STIM (stromal interacting molecule) proteins in the regulation of the store-operated mode of receptor-activated Ca2+ entry. Current models emphasize the role of STIM located in the endoplasmic reticulum membrane, where a Ca2+-binding EF-hand domain within the N-terminal of the protein lies within the lumen and is thought to represent the sensor for the depletion of intracellular Ca2+ stores. Dissociation of Ca2+ from this domain induces the aggregation of STIM to regions of the ER immediately adjacent to the plasma membrane where it acts to regulate the activity of store-operated Ca2+ channels. However, the possible effects of STIM on other modes of receptor-activated Ca2+ entry have not been examined. Here we show that STIM1 also regulates the arachidonic-acid-regulated Ca2+-selective (ARC) channels - receptor-activated Ca2+ entry channels whose activation is entirely independent of store depletion. Regulation of the ARC channels by...