Interhelical interactions within the STIM1 CC1 domain modulate CRAC channel activation

Rathner, Petr; Fahrner, Marc; Cerofolini, Linda; Grabmayr, Herwig; Horvath, Ferdinand; Krobath, Heinrich; Gupta, Agrim; Ravera, Enrico; Fragai, Marco; Bechmann, Matthias; Renger, Thomas; Luchinat, Claudio; Romanin, Christoph; Müller, Norbert

doi:10.1038/s41589-020-00672-8

Cited by 25 publications

(75 citation statements)

References 50 publications

(88 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…6). These results are consistent with NMR studies showing that R304W causes N-terminal extension of the CC1α3 helix, stiffening the CC1α2/α3 linker 29,41 . Release of CC1α1 from CAD, or deletion of the CC1 domain altogether, did not cause a gross change in CAD structure, although it did alter the conformation of the CAD apex (Fig.…”

Section: Discussionsupporting

confidence: 91%

See 1 more Smart Citation

Conformational dynamics of auto-inhibition in the ER calcium sensor STIM1

Lewis

Dorp

Qiu

et al. 2020

Preprint

View full text Add to dashboard Cite

The dimeric ER Ca2+ sensor STIM1 controls store-operated Ca2+ entry (SOCE) through the regulated binding of its CRAC activation domain (CAD) to Orai channels in the plasma membrane. In resting cells, the STIM1 CC1 domain interacts with CAD to suppress SOCE, but the structural basis of this interaction is unclear. Using single-molecule Förster resonance energy transfer (smFRET) and protein crosslinking approaches, we show that CC1 interacts dynamically with CAD in a domain-swapped configuration with an orientation predicted to sequester its Orai- binding region adjacent to the ER membrane. Following ER Ca2+ depletion and release from CAD, cysteine crosslinking indicates that the two CC1 domains become closely paired along their entire length in the active Orai-bound state. These findings provide a structural basis for the dual roles of CC1: sequestering CAD to suppress SOCE in resting cells and propelling it towards the plasma membrane to activate Orai and SOCE after store depletion.

show abstract

Section: Discussionsupporting

confidence: 91%

“…3a, top), as well as between labels at their C-termini (blue histogram in Fig. 3a, bottom), indicating that the CC1α1 domain (a continuous α-helix 23,29 ) is oriented parallel to CC3 in the predominant ctSTIM1 conformation.…”

Section: Cc1α1 Docks Parallel To Cc3 In a Domain-swapped Configuratiomentioning

confidence: 99%

Conformational dynamics of auto-inhibition in the ER calcium sensor STIM1

Lewis

Dorp

Qiu

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…A polybasic lysine-rich domain (PBD) sits at the outermost C-terminus, allowing it to interact with negatively charged phospholipids in the PM (Figure 1) [8,[48][49][50][51]. Additionally, the CC1 domain is further subdivided into three α-helices named α1, α2, and α3 [20][21][22][52][53][54], while CAD/SOAR is separated into four helical regions named Sα1, Sα2, Sα3, and Sα4 [52,55].…”

Section: Stim Proteinsmentioning

confidence: 99%

“…The focus is on competitive interactions of cytosolic domains of STIM. The recently published functional data as well as structural data from nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations have been essential in advancing and complementing the characterization of STIM [15,21,22,30]. Moreover, we report results of ongoing functional investigations that are based on these novel NMR data.…”

Section: Introductionmentioning

confidence: 98%

“…The signal propagates across the transmembrane (TM) domain to the cytosolic C-terminus of STIM [16]. A cascade of conformational changes occurs at the STIM C-terminus, resulting in oligomerization and spatial extension of the protein [16][17][18][19][20][21][22]. The extended STIM protein translocates to the cell periphery and interacts directly with the PM-resident protein Orai [8,23,24].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

STIM Proteins: An Ever-Expanding Family

Grabmayr

Romanin

Fahrner

2020

IJMS

Self Cite

View full text Add to dashboard Cite

Stromal interaction molecules (STIM) are a distinct class of ubiquitously expressed single-pass transmembrane proteins in the endoplasmic reticulum (ER) membrane. Together with Orai ion channels in the plasma membrane (PM), they form the molecular basis of the calcium release-activated calcium (CRAC) channel. An intracellular signaling pathway known as store-operated calcium entry (SOCE) is critically dependent on the CRAC channel. The SOCE pathway is activated by the ligand-induced depletion of the ER calcium store. STIM proteins, acting as calcium sensors, subsequently sense this depletion and activate Orai ion channels via direct physical interaction to allow the influx of calcium ions for store refilling and downstream signaling processes. This review article is dedicated to the latest advances in the field of STIM proteins. New results of ongoing investigations based on the recently published functional data as well as structural data from nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations are reported and complemented with a discussion of the latest developments in the research of STIM protein isoforms and their differential functions in regulating SOCE.

show abstract

Swing‐out opening of stromal interaction molecule 1

et al. 2023

Self Cite

View full text Add to dashboard Cite

Stromal interaction molecule 1 (STIM1) resides in the endoplasmic reticulum (ER) membrane and senses luminal calcium (Ca 2+ ) concentration. STIM1 activation involves a large‐scale conformational transition that exposes a STIM1 domain termed “CAD/SOAR”, ‐ which is required for activation of the calcium channel Orai. Under resting cell conditions, STIM1 assumes a quiescent state where CAD/SOAR is suspended in an intramolecular clamp formed by the coiled‐coil 1 domain (CC1) and CAD/SOAR. Here, we present a structural model of the cytosolic part of the STIM1 resting state using molecular docking simulations that take into account previously reported interaction sites between the CC1α1 and CAD/SOAR domains. We corroborate and refine previously reported interdomain coiled‐coil contacts. Based on our model, we provide a detailed analysis of the CC1‐CAD/SOAR binding interface using molecular dynamics simulations. We find a very similar binding interface for a proposed domain‐swapped configuration of STIM1, where the CAD/SOAR domain of one monomer interacts with the CC1α1 domain of another monomer of STIM1. The rich structural and dynamical information obtained from our simulations reveals novel interaction sites such as M244, I409, or E370, which are crucial for STIM1 quiescent state stability. We tested our predictions by electrophysiological and Förster resonance energy transfer experiments on corresponding single‐point mutants. These experiments provide compelling support for the structural model of the STIM1 quiescent state reported here. Based on transitions observed in enhanced‐sampling simulations paired with an analysis of the quiescent STIM1 conformational dynamics, our work offers a first atomistic model for CC1α1‐CAD/SOAR detachment.

show abstract

Interhelical interactions within the STIM1 CC1 domain modulate CRAC channel activation

Cited by 25 publications

References 50 publications

Conformational dynamics of auto-inhibition in the ER calcium sensor STIM1

Conformational dynamics of auto-inhibition in the ER calcium sensor STIM1

STIM Proteins: An Ever-Expanding Family

Swing‐out opening of stromal interaction molecule 1

Contact Info

Product

Resources

About