COVID19 Spike protein enhances cytosol Ca2+ release from ER for its infection through stimulating the association between ACE2 and STIM1

Abstract The property and signaling mechanisms of the angiotensin produced by ACE2 (angiotensin converting enzyme 2) have been well studied in the renin–angiotensin system. However, less attention has been attracted to the intracellular regulation of ACE2 protein. Using the information which [⁶⁷¹RKKFPLKIFKKPLKK⁶⁸⁵] motif of STIM1(stromal interaction molecule 1 precursor) is able to bind its partner proteins via two acidic amino acids (DD), we recognized that ACE2 contains the short acidic motif binding motif [⁷⁹⁹DD⁸⁰⁰] on its C-terminus. Moreover, we demonstrated that the protein interaction between STIM1 and ACE2 contributes to Ca²⁺ ion release from ER. We recognized that a novel mechanism of ACE2 regulation is modulated through interaction with STIM1, which binds directly to ACE2 as a COVID19 receptor. Further, our findings provide clues why ACE2 helps to release cytoplasmic Ca²⁺ from store-operated Ca²⁺ entry to stimulate viral coat membrane fusion with host plasma membrane, after COVID19 Spike protein binding to ACE2. Our finding also implicates that COVID19 infection enhances cytoplasmic Ca²⁺ ion concentration by releasing Ca²⁺ ion from ER, through its S protein association with its host ACE2 and subsequent STIM1 activation. Thus, our findings may provide the novel target point to prevent COVID19 pandemic recurring and cure it.