More Than Just Simple Interaction between STIM and Orai Proteins: CRAC Channel Function Enabled by a Network of Interactions with Regulatory Proteins

Abstract

The calcium-release-activated calcium (CRAC) channel, activated by the release of Ca2+ from the endoplasmic reticulum (ER), is critical for Ca2+ homeostasis and active signal transduction in a plethora of cell types. Spurred by the long-sought decryption of the molecular nature of the CRAC channel, considerable scientific effort has been devoted to gaining insights into functional and structural mechanisms underlying this signalling cascade. Key players in CRAC channel function are the Stromal interaction molecule 1 (STIM1) and Orai1. STIM1 proteins span through the membrane of the ER, are competent in sensing luminal Ca2+ concentration, and in turn, are responsible for relaying the signal of Ca2+ store-depletion to pore-forming Orai1 proteins in the plasma membrane. A direct interaction of STIM1 and Orai1 allows for the re-entry of Ca2+ from the extracellular space. Although much is already known about the structure, function, and interaction of STIM1 and Orai1, there is growing evidence that CRAC under physiological conditions is dependent on additional proteins to function properly. Several auxiliary proteins have been shown to regulate CRAC channel activity by means of direct interactions with STIM1 and/or Orai1, promoting or hindering Ca2+ influx in a mechanistically diverse manner. Various proteins have also been identified to exert a modulatory role on the CRAC signalling cascade although inherently lacking an affinity for both STIM1 and Orai1. Apart from ubiquitously expressed representatives, a subset of such regulatory mechanisms seems to allow for a cell-type-specific control of CRAC channel function, considering the rather restricted expression patterns of the specific proteins. Given the high functional and clinical relevance of both generic and cell-type-specific interacting networks, the following review shall provide a comprehensive summary of regulators of the multilayered CRAC channel signalling cascade. It also includes proteins expressed in a narrow spectrum of cells and tissues that are often disregarded in other reviews of similar topics.

Calcium Signals during SARS-CoV-2 Infection: Assessing the Potential of Emerging Therapies

“…Cav-1| Caveolin-1 is a protein that seems to have a multitude of functions in the regulation of SOC currents, from the hindrance of SOCE-activation during meiosis, to cell type-specific SOCE activation via the modulation of micro-domains associated with SOCE (for a review on this, see [ 89 ]). Depriving cells of caveolae/caveolin-1 leads to a decrease in viral uptake, viral protein expression, virion release and Cav-1 has been shown to initiate inflammatory reactions by activating leukocytes and nuclear factor-κB [ 90 , 91 ].…”

Store-Operated Calcium Entry in Skeletal Muscle: What Makes It Different?

“…In contrast to the triad, where RyR1 and DHPR do not have a structural function, the MCS containing SOCE are formed by the recruitment of STIM1 to the PM and its binding to Orai1. Several SOCE-interacting proteins were reported, such as SOCE-associated regulatory factor (SARAF), STIM-activating enhancer (STIMATE), partner of STIM (POST), or CRAC regulator 2A (CRACR2A), which serve as fine regulators of Ca 2+ entry (rev in [ 78 ]). To the best of our knowledge, however, none of these regulatory proteins were reported to modulate SOCE in skeletal muscles.…”

Alteration of STIM1/Orai1-Mediated SOCE in Skeletal Muscle: Impact in Genetic Muscle Diseases and Beyond

“…To date, it is known that, in addition to SARAF, there are several auxiliary proteins which, through direct interactions with STIM1 and/or Orai1, favor or reduce the influx of Ca 2+ . For example, several studies have shown that STIMATE (STIM-activating enhancer), an ER/SR transmembrane protein encoded by the TMEM110 gene, interacts directly with STIM1, favoring the conformational change of STIM1 and contributing to maintaining the correct structure of the ER/SR-PM junctions [39][40][41]. Furthermore, it has been shown that STIMATE depletion reduces the formation of STIM1 points at the ER-junctions [39][40][41].…”

“…For example, several studies have shown that STIMATE (STIM-activating enhancer), an ER/SR transmembrane protein encoded by the TMEM110 gene, interacts directly with STIM1, favoring the conformational change of STIM1 and contributing to maintaining the correct structure of the ER/SR-PM junctions [39][40][41]. Furthermore, it has been shown that STIMATE depletion reduces the formation of STIM1 points at the ER-junctions [39][40][41]. Moreover, in skeletal muscle cells, an alternatively spliced variant of STIM1 is also expressed.…”