STIM calcium sensing and conformational change

Abstract

The control of calcium influx at the plasma membrane by endoplasmic reticulum (ER) calcium stores, a process common to invertebrates and vertebrates, is central to physiological calcium signalling and cellular calcium balance. Stromal interaction molecule 1 (STIM1) is a calcium sensor and regulatory protein localized to the ER. ORAI1 is a calcium channel in the plasma membrane (PM). In outline, STIM1 senses an ER-luminal calcium decrease, relocalizes to ER-PM junctions, and recruits and gates ORAI1 channels. Recent work, reviewed here, has offered detailed insight into the process of sensing and communicating ER calcium-store depletion, and particularly into the STIM1 conformational change that is the basis for communication between the ER and the PM.Abstract figure legend A shift in perspective on stromal interaction molecule (STIM) calcium sensing and the mechanism of STIM activation. The endoplasmic reticulum (ER)-luminal domains of the calcium sensors STIM1 and STIM2 bind multiple calcium ions per monomer in the resting state, and the cytoplasmic domains are folded back near the ER membrane. STIM proteins are activated when all bound calcium ions dissociate. This results in luminal domain dimerization and a concerted conformational change that triggers release of the resting CC1-SOAR/CAD interaction and extension of the STIM cytoplasmic domain. This model revises earlier proposed mechanisms of STIM activation that were centred around a single calcium-binding site per monomer and activation driven by unfolding and oligomerization of STIM ER-luminal domains.

STIM Proteins: An Ever-Expanding Family

“…However, recent studies have indicated that a total of 5-6 Ca 2+ ions may be bound to STIM at the same time. Since STIM is a dimeric protein, this would mean that 10-12 Ca 2+ ions are bound per dimer in the inactive state [10,[59][60][61]. The locations of these putative binding sites remain to be elucidated, though their calcium binding seems to be energetically coupled to the EF hand [59].…”

“…Specifically, recently published MD simulations of the STIM1 N-terminus have enabled the prediction of hitherto unknown binding sites for Ca 2+ ions [13]. Even though these MD simulations were carried out at supraphysiological Ca 2+ concentrations and are pending future experimental confirmation, results like these could be the key to finally map the predicted amount of 5-6 Ca 2+ ions to the inactive STIM N-terminus [10,13,[59][60][61]. MD simulations have also been successfully applied to study ER luminal STIM1 GoF mutations associated with tubular aggregate myopathy [63,64], which have also been the subject of investigations at the cellular and whole organism levels [13,65].…”

Oxidative Stress-Induced STIM2 Cysteine Modifications Suppress Store-Operated Calcium Entry

“…Activated STIM protein dimers undergo a conformational change and oligomerize, i.e., form puncta close to the plasma membrane, wherein they, in their open conformation, interact with ORAI channels and activate SOCE (Gudlur et al, 2020;Soboloff et al, 2012). It has been demonstrated that the STIM CC1 domain plays an important role in STIM-STIM interaction and STIM puncta formation (Fahrner et al, 2014;Prakriya and Lewis, 2015).…”

The store-operated Ca 2+ entry complex comprises a small cluster of STIM1 associated with one Orai1 channel

“…This loss of Ca 2+ causes STIM1 to unfurl cytosolic domains that interact with the PM Ca 2+ channel, Orai1, causing its pore to open and Ca 2+ to flow into the cell through the SOCE pathway ( Fig. 1 A ) ( 4 , 5 ). Available evidence suggests that STIM1 must bind to the C-terminal tail of each of the six subunits of an Orai1 channel for optimal activity, with lesser occupancies reducing activity and modifying channel properties ( 6 – 10 ).…”