Inside-out connections: the ER meets the plasma membrane

Abstract

Junctions that connect the endoplasmic reticulum (ER) and the plasma membrane (PM) are unique yet ubiquitous subcellular compartments. Giordano et al. now report that extended synaptotagmins (E-Syts) promote their formation, providing fundamental insight into the molecular machinery controlling ER and plasma membrane crosstalk.

Figure 1.. ER-PM Tethering

ER-PM junctions are ubiquitous cell compartments In which the two membranes are stably kept at a distance of 10 to 20 nm. Giordano et al. (2013) show that three ER-localized proteins, E-Syts, play an important role in tethering the ER to the plasma membrane. Overexpression of E-Syt2 and E-Syt3 connects large regions of the ER to the plasma membrane mediated by E-Syt C2C domains that bind plasma membrane PI(4,5)P2 independent of Ca²⁺. In contrast, E-Syt1 is at basal Ca²⁺ levels not associated with the plasma membrane, but, as the intracellular Ca²⁺ level increases, the C2C domain will bind Ca²⁺ (dashed arrow), resulting in binding to PIP2 in the plasma membrane (black arrow) and trapping of E-Syt1 at the ER-PM junction. This is very different from the regulation of STIM1, for which previous studies showed that STIM1 translocation to these same ER-PM junctions is mediated by lowering of lumenal ER Ca²⁺ levels (illustrated with dashed arrow), which triggers its oligomerization and the exposure of a PI(4,5)P2 binding and an Orai interaction region (black arrow). Giordano et al. (2013) further show that the previously predicted transmembrane region at the N terminus of E-Syts forms a hairpin insertion in the ER membrane, making both N and C termini accessible to the cytosol. All E-Syts have a cytosolic SMP domain, whereas E-Syt1 has five C2 domains compared to three for E-Syt2 and E-Syt3. Domains depicted on STIM1; EF, EF hand; SAM, sterile α motif; CC, coiled-coil; CAD, CRAC activation domain; and PBD, polybasic domain.