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

Lewis, Richard S.; Dorp, Stijn van; Qiu, Ruoyi; Choi, Ucheor B.; Wu, Max C.; Yen, Michelle; Kirmiz, Michael; Brünger, A.T.

doi:10.1101/2020.12.17.423361

Cited by 2 publications

(4 citation statements)

References 53 publications

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“…Our MD simulations and functional data provide novel evidence for the close proximity between the ER membrane and the CAD/SOAR apex. It is worth noting that during the preparation of this manuscript, a similar STIM1 model was published by van Dorp et al [ 71 ]. Their model was created by docking CC1α1 to CAD/SOAR using the Rosetta webserver with distance restraints based on single-molecule FRET measurements.…”

Section: Discussionmentioning

confidence: 99%

“…Figure 7). In the model proposed by van Dorp et al [ 71 ], CAD/SOAR docks to CC1α1 such that the CAD/SOAR apex is closer to the luminal membrane leaflet and the CAD/SOAR apex is apposed to the STIM1 transmembrane helix, suggesting that CAD/SOAR would deeply penetrate the ER membrane. The similarity between those two models reinforces our conclusion that in the quiescent STIM1, the CC1α1-CAD/SOAR clamp is formed such that F394 and its substitutions are located close to and electrostatically interact with the ER membrane.…”

Section: Discussionmentioning

confidence: 99%

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Defects in the STIM1 SOARα2 domain affect multiple steps in the CRAC channel activation cascade

Höglinger

Grabmayr

Maltan

et al. 2021

Cell. Mol. Life Sci.

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The calcium release-activated calcium (CRAC) channel consists of STIM1, a Ca2+ sensor in the endoplasmic reticulum (ER), and Orai1, the Ca2+ ion channel in the plasma membrane. Ca2+ store depletion triggers conformational changes and oligomerization of STIM1 proteins and their direct interaction with Orai1. Structural alterations include the transition of STIM1 C-terminus from a folded to an extended conformation thereby exposing CAD (CRAC activation domain)/SOAR (STIM1-Orai1 activation region) for coupling to Orai1. In this study, we discovered that different point mutations of F394 in the small alpha helical segment (STIM1 α2) within the CAD/SOAR apex entail a rich plethora of effects on diverse STIM1 activation steps. An alanine substitution (STIM1 F394A) destabilized the STIM1 quiescent state, as evident from its constitutive activity. Single point mutation to hydrophilic, charged amino acids (STIM1 F394D, STIM1 F394K) impaired STIM1 homomerization and subsequent Orai1 activation. MD simulations suggest that their loss of homomerization may arise from altered formation of the CC1α1-SOAR/CAD interface and potential electrostatic interactions with lipid headgroups in the ER membrane. Consistent with these findings, we provide experimental evidence that the perturbing effects of F394D depend on the distance of the apex from the ER membrane. Taken together, our results suggest that the CAD/SOAR apex is in the immediate vicinity of the ER membrane in the STIM1 quiescent state and that different mutations therein can impact the STIM1/Orai1 activation cascade in various manners. Graphic abstract Legend: Upon intracellular Ca2+ store depletion of the endoplasmic reticulum (ER), Ca2+ dissociates from STIM1. As a result, STIM1 adopts an elongated conformation and elicits Ca2+ influx from the extracellular matrix (EM) into the cell due to binding to and activation of Ca2+-selective Orai1 channels (left). The effects of three point mutations within the SOARα2 domain highlight the manifold roles of this region in the STIM1/Orai1 activation cascade: STIM1 F394A is active irrespective of the intracellular ER Ca2+ store level, but activates Orai1 channels to a reduced extent (middle). On the other hand, STIM1 F394D/K cannot adopt an elongated conformation upon Ca2+ store-depletion due to altered formation of the CC1α1-SOAR/CAD interface and/or electrostatic interaction of the respective side-chain charge with corresponding opposite charges on lipid headgroups in the ER membrane (right).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Defects in the STIM1 SOARα2 domain affect multiple steps in the CRAC channel activation cascade

Höglinger

Grabmayr

Maltan

et al. 2021

Cell. Mol. Life Sci.

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show abstract

“…Subsequently, STIM1 proteins undergo a conformational change and oligomerize [ 37 , 38 , 42 , 43 ]. Store depletion-induced structural changes propagate from its N-terminal strand to its single TM domain and finally to the C-terminus [ 44 , 45 , 46 , 47 , 48 ]. In particular, STIM1 C-terminus adopts a tight conformation in the quiescent state, which fully extends upon activation to bind to Orai channels in the plasma membrane [ 45 , 49 , 50 , 51 ].…”

Section: Overview Of Store-operated Ca 2+ Entrymentioning

confidence: 99%

“…An inhibitory clamp, especially of the 1st and 3rd coiled-coil region, contributes to the maintenance of the quiescent state [ 45 , 49 , 50 , 51 ]. In the active state, the CC2-CC3 segment, known as the STIM–Orai-activating region (SOAR) or Ca 2+ release-activated Ca 2+ -activating domain (CAD) region, couples to Orai [ 53 , 54 ], while CC1 and CC3 are supposed to stabilize the extended conformation via interacting and oligomerizing with each other [ 9 , 48 ].…”

Section: Overview Of Store-operated Ca 2+ Entrymentioning

confidence: 99%

Isoform-Specific Properties of Orai Homologues in Activation, Downstream Signaling, Physiology and Pathophysiology

Tiffner

Derler

2021

IJMS

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Ca2+ ion channels are critical in a variety of physiological events, including cell growth, differentiation, gene transcription and apoptosis. One such essential entry pathway for calcium into the cell is the Ca2+ release-activated Ca2+ (CRAC) channel. It consists of the Ca2+ sensing protein, stromal interaction molecule 1 (STIM1) located in the endoplasmic reticulum (ER) and a Ca2+ ion channel Orai in the plasma membrane. The Orai channel family includes three homologues Orai1, Orai2 and Orai3. While Orai1 is the “classical” Ca2+ ion channel within the CRAC channel complex and plays a universal role in the human body, there is increasing evidence that Orai2 and Orai3 are important in specific physiological and pathophysiological processes. This makes them an attractive target in drug discovery, but requires a detailed understanding of the three Orai channels and, in particular, their differences. Orai channel activation is initiated via Ca2+ store depletion, which is sensed by STIM1 proteins, and induces their conformational change and oligomerization. Upon STIM1 coupling, Orai channels activate to allow Ca2+ permeation into the cell. While this activation mechanism is comparable among the isoforms, they differ by a number of functional and structural properties due to non-conserved regions in their sequences. In this review, we summarize the knowledge as well as open questions in our current understanding of the three isoforms in terms of their structure/function relationship, downstream signaling and physiology as well as pathophysiology.

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

Cited by 2 publications

References 53 publications

Defects in the STIM1 SOARα2 domain affect multiple steps in the CRAC channel activation cascade

Defects in the STIM1 SOARα2 domain affect multiple steps in the CRAC channel activation cascade

Isoform-Specific Properties of Orai Homologues in Activation, Downstream Signaling, Physiology and Pathophysiology

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