The Short N-terminal Domains of STIM1 and STIM2 Control the Activation Kinetics of Orai1 Channels*

By Diane E. Handy, Gaozhen Hang, J. Scolaro, Nicole Metes, Nadia Razaq, Yi Yang, Joseph Loscalzo. Journal of Biological Chemistry, 2006

658 citations recorded by the source corpus.

STIM1 and STIM2 are dynamic transmembrane endoplasmic reticulum Ca2+ sensors, coupling directly to activate plasma membrane Orai Ca2+ entry channels. Despite extensive sequence homology, the STIM proteins are functionally distinct. We reveal that the short variable N-terminal random coil sequences of STIM1 and STIM2 confer profoundly different activation properties. Using Orai1-expressing HEK293 cells, chimeric replacement of the 43-amino-acid STIM1 N terminus with that of STIM2 attenuates Orai1-mediated Ca2+ entry and drastically slows store-induced Orai1 channel activation. Conversely, the 55-amino-acid STIM2 terminus substituted within STIM1 strikingly enhances both Orai1-mediated Ca2+ entry and constitutive coupling to activate Orai1 channels. Hence, STIM N termini are powerful coupling modifiers, functioning in STIM2 to “brake” the otherwise constitutive activation of Orai1 channels afforded by its high sensitivity to luminal Ca2+.

Subfields: Biochemistry, Plant Science, Sensory Systems

View Paper: https://www.semanticscholar.org/paper/9e25fed5e7acc7a2efe7b7155c36a8b0d00b1d8c

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Citations in the corpus

ALS mutations disrupt phase separation mediated by -helical structure in the TDP-43 low complexity C-terminal domain (2016, background): “Although some TDP-43 variants increase aggregation (Johnson et al., 2009), two mutations (Q331K and M337V) can induce motor neuron defects in mice in the absence of inclusion formation(Arnold et al., 2013; D'Alton et al., 2014) and do not effect TDP-43 aggregation(Jiang et al., 2016).”
The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease (2012, background): “In isolation, TDP-43 is intrinsically aggregationprone , and deleting the prion-like domain eliminates this behavior (Johnson et al., 2009 ).”
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis (2019, background): “C-Terminal Fragmentation of TDP-43 The generation of C-terminal fragments of TDP-43 via proteolytic cleavages by the caspase and calpain proteases seems to be one of the prominent toxicity generating mechanisms, as we have discussed, previously in the “C-terminal domain” section (Zhang et al., 2007,”
TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS (2020, background): “The C-terminal glycine-rich domain encodes a prion-like structure that can potentiate cytoplasmic aggregation (Johnson et al., 2009).”
Stress granules as crucibles of ALS pathogenesis (2013, background): “, 2010) might drive dysregulated assembly of inappropriate fibrillar aggregates (Johnson et al., 2009; Sun et al., 2011), which perturb the localization of messenger RNPs (mRNPs) required for RNA processing and decay, thereby interfering with RNA sorting.”
Tar DNA Binding Protein-43 (TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue (2010, background): “TDP-43 is an intrinsically aggregation prone protein [29].”
ALS‐associated fused in sarcoma (FUS) mutations disrupt Transportin‐mediated nuclear import (2010, background): “Moreover, expression of TDP-43 in yeast and neuroblastoma cells suggested that the fALS-associated mutations might increase the aggregation propensities of TDP-43 rather than impairing its nuclear transport (Johnson et al, 2009; Nonaka et al, 2009).”
TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. (2010, background): “For example, early studies of hTDP-43 mutants (233,234) in yeast reported that foci of aggregated protein were better determinants of cellular toxicity than diffuse cytosolic staining, but this was not seen for inclusion body formation in the cytoplasm of primary neurons (223) or in Drosophila motor”
Store-Operated Calcium Channels. (2015, neutral): “Chimeric swap experiments show that the NH2-terminal region of STIM2 reduces the speed and extent of CRAC channel activation relative to that of STIM1 (452).”