STIM1 and lipid interactions at ER-PM contact sites

Abstract

Store-operated calcium (Ca2+) entry (SOCE) represents a major route of Ca2+ permeation across the plasma membrane (PM) in non-excitable cells, which plays an indispensable role in maintaining intracellular Ca2+ homeostasis. This process is orchestrated through the dynamic coupling between the endoplasmic reticulum (ER)-localized Ca2+ sensor stromal interaction molecule 1 (STIM1) and the PM-resident ORAI1 channel. Upon depletion of ER Ca2+ stores, STIM1 undergoes conformational rearrangements and oligomerization, leading to translocation of STIM1-containing ER membrane towards the PM. This movement is facilitated by the physical interaction between positively charged cytosolic domains within STIM1 and negatively charged phospholipids embedded in the PM, ultimately enabling its binding to and activation of the PM-embedded ORAI1 channel. In this mini-review, we provide an overview of STIM1-mediated Ca2+ signaling at ER-PM contact sites, highlighting the regulatory roles of phospholipids in the inner leaflet and sphingolipids in the outer leaflet of the PM. We also discuss the development of molecular tools that enable real-time visualization and manipulation of membrane contact sites (MCSs) at ER-PM junctions. Lastly, we highlight recent progress in developing targeted therapies for human diseases linked to STIM1 mutations and dysregulated Ca2+ signaling at ER-PM MCSs.