Stromal interaction molecule 2 (STIM2) is a transmembrane protein that is present in the endoplasmic reticulum (ER) and regulates store-operated Ca²⁺ entry (SOCE). STIM2 is the predominant protein in murine dendritic cells, mammary epithelial cells during lactation, human melanocytes, mouse spinal cord dorsal horn neurons, forebrain and hippocampus. The human STIM2 protein is encoded by STIM2 gene that is located on chromosome 4 region 15.2 (4p15.2). Alternative splicing produces three mRNA isoforms, the already known variant (Stim2.2, also STIM2α), a new shorter variant (Stim2.3), and a third larger splicing variant (Stim2.1; also STIM2β). Protein translation produces a single transmembrane proprotein that contains an endoplasmic reticulum (ER) signal peptide, a highly Ca²⁺ binding canonical EF-hand motif (cEF-hand) in the N-terminal region, followed by a hidden EF-hand motif (hEF-hand) and a sterile alpha motif (SAM), both located in the cavity area of the ER. The cEF-hand motif is a Ca²⁺sensor, while the hEF-hand and SAM domains are critical for maintaining the stability of the N-terminal region and oligomerization between the STIM proteins, respectively. The C-terminal region is located in the cytoplasmic compartment and separated from the N-terminal region by a single transmembrane domain. The C-terminal region contains the ezrin/radixin/moesin domain and is highly conserved in the STIM isoform, which includes two coiled-coil structures. This region mediates the interaction between the STIM1 and TRPC Ca²⁺ channels.
|Basic Information of STIM2|
|Protein Name||Stromal interaction molecule 2|
|Organism||Homo sapiens (Human)|
In most cell types, the release of ER Ca²⁺ triggers storage operation of Ca²⁺ entry (SOCE), a form of Ca²⁺ influx in various cells which is regulated by the ER-resident STIM proteins. Stromal interaction molecule 1 (STIM1, a Ca²⁺ sensor) along with Orai1 (a Ca²⁺ entry channel) are the main proteins responsible for SOCE. STIM2 is a second ER-localized Ca²⁺ sensor protein that has been associated with SOCE and Ca²⁺ signaling. However, STIM2 is a poor activator of Orai1 and SOCE as compared to STIM1. STIM2 appears to play a complementary role in the control of intracellular Ca²⁺ homeostasis when STIM1 is prominently present. STIM2 can also act as an adaptor protein and increase the sensitivity of STIM1 to Ca²⁺ changes in ER by promoting recruitment of STIM1 to the endoplasmic reticulum (ER) and plasma membrane (PM) (ER-PM) junctions. In addition, STIM2 participates in the turnover of cholesterol content in neuronal PM and plays an important role in the nervous system. Moreover, STIM2 has also been proposed as a relevant player in pathological conditions related to aging, Alzheimer's and Huntington's diseases, autoimmune disorders and cancer.
Fig.1 The molecular structure of the STIM2 variant. The N-terminal region of the ER cavity includes a Ca²⁺ binding canonical EF-hand motif (cEF), hidden EF-hand (hEF) motif and a sterile alpha motif (SAM). The cytoplasmic C-terminal region includes CC regions (CC1 and CC2). (Rosado, 2015)
This review summarizes the role of STIM2 in the nervous system, the immune system, and anti-aging and cancer-related pathological conditions, and updates current knowledge of STIM2 function.
This article suggests that STIM2 promotes synaptic delivery and AMPA receptor removal, and regulates activity-dependent changes in synaptic strength through a unique communication pattern between endoplasmic reticulum and synapses.
This article suggests that expression of STIM2 protein rescues calcium-calmodulin-dependent kinase II (CaMKII) activity and protects mushroom spines from amyloid toxicity in vitro and in vivo.
This article reveals that alternative splicing of the STIM protein family creates negative and positive regulators of SOCE to shape the amplitude and dynamics of Ca(2+) signals.
This article suggests that STIM2 regulates GluA1 phosphorylation by coupling PKA to AMPAR in a SOCE-independent manner and promotes cAMP-dependent GluA1 surface delivery through a combination of exocytosis and endocytosis.
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