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Comprehensive mutational characterization of the calcium-sensing STIM1 EF-hand reveals residues essential for structure and function

ABSTRACT: Comprehensive mutational characterization of the calcium-sensing STIM1 EF-hand reveals residues essential for structure and function

PROVIDER: PRJNA1214815 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32095200_1.fastq.gz	Fastqsanger.gz
	SRR32095200_2.fastq.gz	Fastqsanger.gz
	SRR32095201_1.fastq.gz	Fastqsanger.gz
	SRR32095201_2.fastq.gz	Fastqsanger.gz
	SRR32095202_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Comprehensive mutational characterization of the calcium-sensing STIM1 EF-hand reveals residues essential for structure and function

Project description:Calcium signaling is a fundamental molecular means of cellular regulation. Store operated calcium entry (SOCE) is a major intracellular signaling module, wherein calcium release from the endoplasmic reticulum triggers transmembrane STIM1 proteins to conformationally shift and oligomerize to prompt calcium influx from the extracellular environment. STIM1 senses ER calcium concentrations with its canonical EF-hand domain, and missense variants can dysregulate SOCE and cause Tubular Aggregate Myopathy, Stormorken Syndrome or immunodeficiency. Few STIM1 EF-hand variants are characterized, obscuring how STIM1 sequence controls its function, and hampering clinical interpretation of STIM1 variants observed in patients. We leveraged fitness costs caused by overexpression of STIM1 variants in cultured human cells to functionally characterize 706 of the 720 possible single amino acid variants of the STIM1 canonical EF-hand. The calcium-coordinating EF-hand residues exhibited varying mutational patterns. The trailing helix possessed a core of immutable residues, even depleting during library propagation in bacteria, implicating residues normally restraining STIM1 aggregation. The leading helix only exhibited toxicity in cells with endogenous STIM1, implicating a multimerization-dependent STIM1 regulatory module. No cytotoxic STIM1 variants were observed in healthy human populations. Some disease-associated variants had low scores, but most pathogenic variants were not overtly cytotoxic in our assay. We demonstrate that orthogonal measurements for STIM1 oligomerization, cytoplasmic calcium influx, and cellular stress complement the cytotoxicity phenotypes to enhance variant understanding. Collectively, these data reveal the complex molecular roles embedded in the STIM1 canonical EF-hand sequence for its function in promoting calcium signaling through SOCE.

2025-01-27 | GSE287849 | GEO

Comprehensive mutational characterization of the calcium-sensing STIM1 EF-hand reveals residues essential for structure and function.

| S-EPMC11785200 | biostudies-literature

STIM1 Mediates Calcium-dependent Epigenetic Reprogramming in Pancreatic Cancer [mRNAseq_siSTIM1_Thap]

Project description:We characterized Gemcitabine resistant pancreatic cancer tumors and show that the co-amplification of RRM1 and STIM1 confers novel and independent properties to gemcitabine resistant cells. The upregulation of RRM1 drives gemcitabine resistance, while the amplification of STIM1 leads to increased cytosolic calcium upon stress, eliciting ER stress resistance and NFAT activation.

2021-01-14 | GSE152123 | GEO

STIM1 Mediates Calcium-dependent Epigenetic Reprogramming in Pancreatic Cancer [mRNAseq_Par_GemR]

2021-01-14 | GSE152121 | GEO

STIM1 Mediates Calcium-dependent Epigenetic Reprogramming in Pancreatic Cancer [ChIPseq_siSTIM1_Thap]

2021-01-14 | GSE152120 | GEO

STIM1 Mediates Calcium-dependent Epigenetic Reprogramming in Pancreatic Cancer [ChIPseq_Par_GemR]

2021-01-14 | GSE152119 | GEO

STIM1 Mediates Calcium-dependent Epigenetic Reprogramming in Pancreatic Cancer [mRNAseq_PDX]

2021-01-14 | GSE154909 | GEO

STIM1 Translocation to The Nucleus Protects Cells from DNA Damage

Project description:DNA damage represents a challenge for cells as this damage must be eliminated to preserve cell viability and the transmission of genetic information. To reduce or eliminate unscheduled chemical modifications in genomic DNA, an extensive signaling network, known as the DNA damage response (DDR) pathway, ensures this repair. In this work, and by means of a proteomic analysis aimed at the study of the STIM1 protein interactome, we have found that STIM1 is closely related to the protection from endogenous DNA damage, replicative stress, as well as in the response to interstrand crosslinks (ICLs). Here we show that STIM1 has a nuclear localization signal (NLS) that mediates its translocation to the nucleus, and that this translocation and the association of STIM1 to chromatin is enhanced in response to mitomycin C (MMC), an ICL-inducing agent. Consequently, STIM1-deficient cell lines show a higher level of basal DNA damage, replicative stress, and a higher sensitivity to MMC. We show that STIM1 normalizes FANCD2 protein levels in the nucleus, explaining the increased sensitivity to MMC in STIM1-KO cells. Our results show for the first time a nuclear function for the endoplasmic reticulum protein STIM1 and increase the number of genes involved in DNA repair.

2023-12-22 | PXD041181 | Pride

Expression profile of select glucose and lipid metabolic genes mediated by STIM1 knockout, or STIM1 knockout plus Snail1 overexpression in SMMC7721 cells

Project description:To investigate the altered glucose and lipid metabolism genes after STIM1 knockout (STIM1 KO) or STIM1 knockout plus Snail1 OE (STIM1 KO+Snail1 OE) in SMMC7721 cells. STIM1 KO-SMMC7721 cells were constructed by CRISPR/Cas9, and STIM1 KO+Snail1 OE-SMMC7721 cells was established via lentiviral Infection of Snail1 overexpression in STIM1 KO-SMMC7721 cells. The cells mentioned above were cultured in DMEM supplemented with 10% (v/v) FBS at 37 °C in 5% CO2. When the cells grow to 60~70% confluent, total RNA was extracted by using Trizol (TAKARA, Japan). Reverse transcription was performed from 1μg total RNA using PrimeScript™ RT reagent Kit with gDNA Eraser (TAKARA), Quantitative real-time PCR were performed (CFX386, BioRad) with 40 cycles at 95 °C for 10 seconds, 59 °C for 20 seconds and 72 °C for 30 seconds.

2020-04-07 | GSE148129 | GEO

The leucine zipper EF-hand containing transmembrane protein-1 EF-hand is a tripartite calcium, temperature, and pH sensor.

Project description:Leucine Zipper EF-hand containing transmembrane protein-1 (LETM1) is an inner mitochondrial membrane protein that mediates mitochondrial calcium (Ca2+ )/proton exchange. The matrix residing carboxyl (C)-terminal domain contains a sequence identifiable EF-hand motif (EF1) that is highly conserved among orthologues. Deletion of EF1 abrogates LETM1 mediated mitochondrial Ca2+ flux, highlighting the requirement of EF1 for LETM1 function. To understand the mechanistic role of this EF-hand in LETM1 function, we characterized the biophysical properties of EF1 in isolation. Our data show that EF1 exhibits α-helical secondary structure that is augmented in the presence of Ca2+ . Unexpectedly, EF1 features a weak (~mM), but specific, apparent Ca2+ -binding affinity, consistent with the canonical Ca2+ coordination geometry, suggested by our solution NMR. The low affinity is, at least in part, due to an Asp at position 12 of the binding loop, where mutation to Glu increases the affinity by ~4-fold. Further, the binding affinity is sensitive to pH changes within the physiological range experienced by mitochondria. Remarkably, EF1 unfolds at high and low temperatures. Despite these unique EF-hand properties, Ca2+ binding increases the exposure of hydrophobic regions, typical of EF-hands; however, this Ca2+ -induced conformational change shifts EF1 from a monomer to higher order oligomers. Finally, we showed that a second, putative EF-hand within LETM1 is unreactive to Ca2+ either in isolation or tandem with EF1. Collectively, our data reveal that EF1 is structurally and biophysically responsive to pH, Ca2+ and temperature, suggesting a role as a multipartite environmental sensor within LETM1.

| S-EPMC7980503 | biostudies-literature

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