The TAM-associated STIM1I484R mutation increases ORAI1 channel function due to a reduced STIM1 inactivation break and an absence of microtubule trapping

Kim, Jihee; Carreras-Sureda, Amado; Didier, Monica; Henry, Christopher; Frieden, Maud; Demaurex, Nicolas

doi:10.1016/j.ceca.2022.102615

Cited by 8 publications

(14 citation statements)

References 47 publications

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“…57 Similarly, a very recent paper showed that mutation at I484R residue lead to truncation of STIM1, which presented normal fast calcium-dependent inactivation but reduced SCDI. 58 Results obtained from the coimmunoprecipitation experiments between s-STIM1 (478) and SARAF in HEK293 cells, reinforce the idea of that s-STIM1 found in neonatal platelets avoid SCDI. In line with these data, DAMI and MEG01 cells overexpressing SARAF alone presented enhanced SCDI mechanism, with the exception of those cells where we overexpressed s-STIM1 (478).…”

Section: Discussionmentioning

confidence: 58%

CAPN1 (Calpain1)-Dependent Cleavage of STIM1 (Stromal Interaction Molecule 1) Results in an Enhanced SOCE (Store-Operated Calcium Entry) in Human Neonatal Platelets

Berna‐Erro

Ramesh

Delgado³

et al. 2023

ATVB

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Background: Altered intracellular Ca 2+ homeostasis in neonatal platelets has been previously reported. This study aims to examine the changes in the Ca 2+ entry through the store-operated calcium entry (SOCE) mechanism in neonatal platelets. Methods: Human platelets from either control women, mothers, and neonates were isolated and, following, were fixed after being treated as required. Platelet samples were analyzed by Western blotting, qRT-PCR, and MALDITOF/TOF. Ca 2+ homeostasis was also determined. Culture cells were used as surrogated of platelets to overexpress the proteins of interest to reproduce the alterations observed in platelets. Results: Altered thapsigargin-evoked SOCE, alternative molecular weight form of STIM1 (stromal interaction molecule 1; s-STIM1 [short STIM1 isoform (478 aa)], around 60 kDa) and overexpression of SARAF (SOCE-associated regulatory factor [TMEM66]) were found in neonatal platelet as compared to maternal and control women platelets. s-STIM1 may result due to CAPN1 (calpain1)-dependent processing, as confirmed in platelets and MEG01 cells by using calpeptin and overexpressing CAPN1, respectively. In HEK293 (STIM1 and STIM2 [stromal interaction molecule 2] double knockout) cells transfected either with c-STIM1 (canonical STIM1 [685 aa]), s-STIM1 (478), STIM1B (540), and CAPN1 overexpression plasmids, we found s-STIM1 and c-STIM1, except in cells overexpressing s-STIM1 (478) that lacked CAPN1 target residues. These results and the in silico analysis, lead us to conclude that STIM1 is cleaved at Q496 by CAPN1. Ca 2+ imaging analysis and coimmunoprecipitation assay using MEG01 and HEK293 cells overexpressing SARAF together with s-STIM1 (478) reported a reduced slow Ca 2+ –dependent inactivation, so reproducing the Ca 2+ -homeostasis pattern observed in neonatal platelets. Conclusions: CAPN1 may cleave STIM1 in neonatal platelets, hence, impairing SARAF coupling after SOCE activation. S-STIM1 may avoid slow Ca 2+ –dependent inactivation and, subsequently, result in an enhanced thapsigargin-evoked SOCE as observed in neonatal platelets.

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Section: Discussionmentioning

confidence: 58%

CAPN1 (Calpain1)-Dependent Cleavage of STIM1 (Stromal Interaction Molecule 1) Results in an Enhanced SOCE (Store-Operated Calcium Entry) in Human Neonatal Platelets

Berna‐Erro

Ramesh

Delgado³

et al. 2023

ATVB

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“…Surprisingly, internal deletion of these residues (Δ675-710), decreased SOCE. An increase in STIM1 function upon larger C-terminal deletion has recently been described for the TAM associated gain-of-function mutation STIM1 I484R , leading to termination of translation at residue 502, abrogating MT binding sites and PBD [42]. Here, interpretation of its activated phenotype involves a potential disabled binding of the inhibitory domain (ID) of STIM1 to the CC1 region and disabled binding of STIM1 to SARAF, an accessory protein which maintains STIM proteins in the closed and inactive conformation [43, 44], or a combination of both.…”

Section: Discussionmentioning

confidence: 99%

A better brain? Alternative spliced STIM2 in hominoids arises with synapse formation and creates a gain-of-function variant

Poth¹,

Trang

Foerderer³

et al. 2023

Preprint

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Balanced Ca2+ homeostasis is essential for cellular functions. STIM2 mediated Store-Operated Ca2+ Entry (SOCE) regulates cytosolic and ER Ca2+ concentrations, stabilizes dendritic spine formation and drives presynaptic spontaneous transmission and ER stress in neurons. Recently identified alternative spliced variants expand the STIM protein repertoire, uncover unique functions and facilitate our understanding of tissue specific regulation of SOCE. Here, we describe an addition to this repertoire, a unique short STIM2 variant (STIM2.3/STIM2G) present only in old world monkeys and humans with expression in humans starting with the beginning of brainwave activity and upon synapse formation within the cerebral cortex. In contrast to the short STIM1B variant, STIM2.3/STIM2G increases SOCE upon stimulation independently of specific spliced in residues. Basal cluster formation is reduced and analyses of several additional deletion and point mutations delineate the role of functional motifs for Ca2+ entry, NFAT activation and changes in neuronal gene expression. In addition, STIM2.3/STIM2G shows reduced binding and activation of the energy sensor AMPK. In the context of reduced STIM2.3 splicing seen in postmortem brains of patients with Huntingtons disease, our data suggests that STIM2.3/STIM2G is an important regulator of neuronal Ca2+ homeostasis, potentially involved in synapse formation/maintenance and evolutionary expansion of brain complexity.

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“…This blocks STIM1 to bind to ORAI1, which then enables STIM1 trapping by microtubules and interferes slow Ca 2+ -dependent inhibition. This might provide a mechanistic explanation of why TAM patients with this mutation receive muscular defects [ 39 ].…”

Section: Orai/stim Channel Complexes In Human Diseasesmentioning

confidence: 99%

ORAI Calcium Channels: Regulation, Function, Pharmacology, and Therapeutic Targets

Rubaiy

2023

Pharmaceuticals

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The changes in intracellular free calcium (Ca2+) levels are one of the most widely regulators of cell function; therefore, calcium as a universal intracellular mediator is involved in very important human diseases and disorders. In many cells, Ca2+ inflow is mediated by store-operated calcium channels, and it is recognized that the store-operated calcium entry (SOCE) is mediated by the two partners: the pore-forming proteins Orai (Orai1-3) and the calcium store sensor, stromal interaction molecule (STIM1-2). Importantly, the Orai/STIM channels are involved in crucial cell signalling processes such as growth factors, neurotransmitters, and cytokines via interaction with protein tyrosine kinase coupled receptors and G protein-coupled receptors. Therefore, in recent years, the issue of Orai/STIM channels as a drug target in human diseases has received considerable attention. This review summarizes and highlights our current knowledge of the Orai/STIM channels in human diseases and disorders, including immunodeficiency, myopathy, tubular aggregate, Stormorken syndrome, York platelet syndrome, cardiovascular and metabolic disorders, and cancers, as well as suggesting these channels as drug targets for pharmacological therapeutic intervention. Moreover, this work will also focus on the pharmacological modulators of Orai/STIM channel complexes. Together, our thoughtful of the biology and physiology of the Orai/STIM channels have grown remarkably during the past three decades, and the next important milestone in the field of store-operated calcium entry will be to identify potent and selective small molecules as a therapeutic agent with the purpose to target human diseases and disorders for patient benefit.

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The TAM-associated STIM1I484R mutation increases ORAI1 channel function due to a reduced STIM1 inactivation break and an absence of microtubule trapping

Cited by 8 publications

References 47 publications

CAPN1 (Calpain1)-Dependent Cleavage of STIM1 (Stromal Interaction Molecule 1) Results in an Enhanced SOCE (Store-Operated Calcium Entry) in Human Neonatal Platelets

CAPN1 (Calpain1)-Dependent Cleavage of STIM1 (Stromal Interaction Molecule 1) Results in an Enhanced SOCE (Store-Operated Calcium Entry) in Human Neonatal Platelets

A better brain? Alternative spliced STIM2 in hominoids arises with synapse formation and creates a gain-of-function variant

ORAI Calcium Channels: Regulation, Function, Pharmacology, and Therapeutic Targets

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