A dual topology of STIM1 at the plasma membrane regulates calcium constitutive entry

STIM1, a type I transmembrane protein characterized by its extracellular N-terminal domain (STIM1PM), was initially identified as a plasma membrane (PM)-localized protein with tumor growth suppressor activity. Subsequent studies have identified a role for STIM1PM in the regulation of store-independent Ca2+ entry pathways including arachidonic acid-regulated Ca2+ (ARC) channels and constitutive Ca2+ entry (CCE). Mechanistically, N-glycosylation facilitates STIM1PM trafficking and stability at the PM. In this study, we demonstrate that STIM1PM uniquely exhibits dual topology at the PM, presenting both the expected type I orientation and an alternative type II orientation. Notably, we found that both orientations of STIM1PM contribute to CCE regulation. Our results confirm that N-glycosylation promotes the N-terminal-out orientation of STIM1PM, however, here we found it also modulates it’s the receptor’s dual topology. Our findings reveal that STIM1PM displays dual topology and regulate CCE.