Enhancement of Ca2+ Release from Store-Operated Ca2+ Entry by Corona Virus Disease 2019 (COVID-19) Spike (S) Protein

Functions and viral infection mechanisms of coronavirus disease 2019 (COVID-19) have been recently investigated extensively, focusing on Spike (S) protein together with its receptor, ACE2. Although their relationships with COVID-19 are obvious, less attention has been paid to intracellular regulation of S protein-protein interaction.

Here, we identified STIM1 (Stromal Interaction Molecule 1 Precursor) as a novel binding protein of S protein for the first time. Their association was further characterized. We found that S (¹²⁵⁹DD¹²⁶⁰) acidic motif specifically interacted with STIM1 C-terminal basic motif (⁶⁷¹RKKFPLKIFKKPLKK⁶⁸⁵). Both motifs were demonstrated to be essential for STIM1 and S protein interaction using immune precipitation and immune blotting and confocal co-localization. We also elucidated that the association between the acidic tail motif of S protein and the C-terminal basic motif of STIM1 promoted Ca²⁺ cytoplasmic release from the Store- Operated Ca²⁺ Ion Entry (SOCE) by disrupting STIM1 function, suggesting that disrupting STIM1 function by S protein was one of its mode of actions for COVID-19 infection.

For the first time, we demonstrated that S protein played a role as a Ca²⁺ ion releasing enhancer for COVID-19 infection from SOCE through interrupting normal STIM1’s roles. Our findings may provide one of the new ways for curing or preventing COVID-19 pandemic recurrence.

Background: We noticed the presence of coronavirus disease 2019 (COVID-19) spike (S) protein acidic tail (¹²⁵⁹DD¹²⁶⁰) and STIM1 (Stromal Interaction Molecule 1 Precursor) C-terminal basic amino acid domain (⁶⁷¹RKKFPLKIFKKPLKK⁶⁸⁵) by the consensus amino acid sequence survey.

Result: Association between S protein and STIM1 increases intracellular Ca²⁺ in the human cell, resulting in apoptosis and autophagy. Conclusion: Interaction between S protein and STIM1 causes the toxicity of COVID-19.

Significance: Binding between S protein and STIM1 that promotes the intracellular Ca²⁺ after its infection for the membrane fusion between host and COVID-19, assuming one of drug developing target points.