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

TL;DR

STIM1 at the cell membrane has two orientations and helps regulate calcium entry, which is important for cell signaling.

Contribution

This study reveals that STIM1PM has a dual topology at the plasma membrane and regulates constitutive calcium entry.

Findings

STIM1PM exhibits both type I and type II membrane orientations.

N-glycosylation influences STIM1PM's dual topology and stability.

Both orientations of STIM1PM contribute to constitutive calcium entry regulation.

Abstract

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.

The online version contains supplementary material available at 10.1007/s00018-026-06141-0.

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