Structural elements of stromal interaction molecule function

Novello, Matthew J.; Zhu, Jinhui; Feng, Qingping; Ikura, Mitsuhiko; Stathopulos, Peter B.

doi:10.1016/j.ceca.2018.04.006

Cited by 35 publications

(24 citation statements)

References 84 publications

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“…Next, we searched for the signaling molecules responsible for synaptic decay of MCs in AD mice by focusing on the altered expression of synaptic genes in MCs of AD mice at 6 months old of age. STIM2, as a member of the stromal interaction molecule family, was interested as it detects Ca 2+ homeostasis in the endoplasmic reticulum and involves Ca 2+ ‐dependent cellular events (Novello, Zhu, Feng, Ikura, & Stathopulos, 2018; Pchitskaya et al, 2017). A dramatic reduction of STIM2 was verified by single‐cell PCR and Western blots in MCs from AD mice at 6 months old of age (Figure 5a–c).…”

Section: Resultsmentioning

confidence: 99%

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Mossy cell synaptic dysfunction causes memory imprecision via miR‐128 inhibition of STIM2 in Alzheimer's disease mouse model

Deng

Zhang

et al. 2020

Aging Cell

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Recently, we have reported that dentate mossy cells (MCs) control memory precision via directly and functionally innervating local somatostatin (SST) inhibitory interneurons. Here, we report a discovery that dysfunction of synaptic transmission between MCs and SST cells causes memory imprecision in a mouse model of early Alzheimer's disease (AD). Single‐cell RNA sequencing reveals that miR‐128 that binds to a 3′UTR of STIM2 and inhibits STIM2 translation is increasingly expressed in MCs from AD mice. Silencing miR‐128 or disrupting miR‐128 binding to STIM2 evokes STIM2 expression, restores synaptic function, and rescues memory imprecision in AD mice. Comparable findings are achieved by directly engineering MCs with the expression of STIM2. This study unveils a key synaptic and molecular mechanism that dictates how memory maintains or losses its details and warrants a promising target for therapeutic intervention of memory decays in the early stage of AD.

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Section: Resultsmentioning

confidence: 99%

“…STIM2 is a member of the stromal interaction molecule family and detects Ca 2+ homeostasis in the endoplasmic reticulum and involves Ca 2+ ‐dependent cellular events (Novello et al, 2018; Pchitskaya et al, 2017). In our present study, we have shown that STIM2 expression is dramatically reduced in MCs from AD mice at 6 months old of age.…”

Section: Discussionmentioning

confidence: 99%

Mossy cell synaptic dysfunction causes memory imprecision via miR‐128 inhibition of STIM2 in Alzheimer's disease mouse model

Deng

Zhang

et al. 2020

Aging Cell

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“…STIMs are localized to the ER membrane and act as Ca 2+ sensors via their luminal EF-hand Ca 2+ -binding site. Upon a decrease in Ca 2+ levels in the ER lumen, the EF-hand changes its conformation, leading to the formation of clusters of STIM molecules and their translocation to the plasma membrane [ 2 , 3 , 4 ]. In the plasma membrane, STIM proteins form complexes with plasma membrane channels, including Orai (Orai1, Orai2, or Orai3) [ 5 ] and TRP (especially members of the TRPC and TRPV families) [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Knockout of stim2a Increases Calcium Oscillations in Neurons and Induces Hyperactive-Like Phenotype in Zebrafish Larvae

Gupta

Wasilewska

Palchevska

et al. 2020

IJMS

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Stromal interaction molecule (STIM) proteins play a crucial role in store-operated calcium entry (SOCE) as endoplasmic reticulum Ca2+ sensors. In neurons, STIM2 was shown to have distinct functions from STIM1. However, its role in brain activity and behavior was not fully elucidated. The present study analyzed behavior in zebrafish (Danio rerio) that lacked stim2a. The mutant animals had no morphological abnormalities and were fertile. RNA-sequencing revealed alterations of the expression of transcription factor genes and several members of the calcium toolkit. Neuronal Ca2+ activity was measured in vivo in neurons that expressed the GCaMP5G sensor. Optic tectum neurons in stim2a−/− fish had more frequent Ca2+ signal oscillations compared with neurons in wildtype (WT) fish. We detected an increase in activity during the visual–motor response test, an increase in thigmotaxis in the open field test, and the disruption of phototaxis in the dark/light preference test in stim2a−/− mutants compared with WT. Both groups of animals reacted to glutamate and pentylenetetrazol with an increase in activity during the visual–motor response test, with no major differences between groups. Altogether, our results suggest that the hyperactive-like phenotype of stim2a−/− mutant zebrafish is caused by the dysregulation of Ca2+ homeostasis and signaling.

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“…Together, the three CCs and ID fall within the Orai-activating STIM fragment (OASF) and are critical for mediating a compact to extended conformation integral to SOCE activation [ 27 ]. The Ser/Pro-rich region can be phosphorylated at several sites, promoting or inhibiting SOCE activation (recently reviewed in [ 28 ]). Since STIM1 is the primary regulator of SOCE [ 3 , 29 , 30 ], the specific conformational rearrangements which occur in the STIM1 conserved domains for SOCE activation are well-defined.…”

Section: Introductionmentioning

confidence: 99%

The 2β Splice Variation Alters the Structure and Function of the Stromal Interaction Molecule Coiled-Coil Domains

Chung

Zhang

Stathopulos

2018

IJMS

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Stromal interaction molecule (STIM)-1 and -2 regulate agonist-induced and basal cytosolic calcium (Ca2+) levels after oligomerization and translocation to endoplasmic reticulum (ER)-plasma membrane (PM) junctions. At these junctions, the STIM cytosolic coiled-coil (CC) domains couple to PM Orai1 proteins and gate these Ca2+ release-activated Ca2+ (CRAC) channels, which facilitate store-operated Ca2+ entry (SOCE). Unlike STIM1 and STIM2, which are SOCE activators, the STIM2β splice variant contains an 8-residue insert located within the conserved CCs which inhibits SOCE. It remains unclear if the 2β insert further depotentiates weak STIM2 coupling to Orai1 or independently causes structural perturbations which prevent SOCE. Here, we use far-UV circular dichroism, light scattering, exposed hydrophobicity analysis, solution small angle X-ray scattering, and a chimeric STIM1/STIM2β functional assessment to provide insights into the molecular mechanism by which the 2β insert precludes SOCE activation. We find that the 2β insert reduces the overall α-helicity and enhances the exposed hydrophobicity of the STIM2 CC domains in the absence of a global conformational change. Remarkably, incorporation of the 2β insert into the STIM1 context not only affects the secondary structure and hydrophobicity as observed for STIM2, but also eliminates the more robust SOCE response mediated by STIM1. Collectively, our data show that the 2β insert directly precludes Orai1 channel activation by inducing structural perturbations in the STIM CC region.

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Structural elements of stromal interaction molecule function

Cited by 35 publications

References 84 publications

Mossy cell synaptic dysfunction causes memory imprecision via miR‐128 inhibition of STIM2 in Alzheimer's disease mouse model

Mossy cell synaptic dysfunction causes memory imprecision via miR‐128 inhibition of STIM2 in Alzheimer's disease mouse model

Knockout of stim2a Increases Calcium Oscillations in Neurons and Induces Hyperactive-Like Phenotype in Zebrafish Larvae

The 2β Splice Variation Alters the Structure and Function of the Stromal Interaction Molecule Coiled-Coil Domains

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