STIM–ORAI Interactions That Control the CRAC Channel

Gudlur, Aparna; Zhou, Yubin; Hogan, Patrick G.

doi:10.1016/b978-0-12-407870-3.00002-0

Cited by 42 publications

(43 citation statements)

References 70 publications

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“…Studies reveal that the holo-STIM1 molecule unfolds during the store-induced activation process to expose the SOAR moiety [1, 68]. The isolated STIM1ct molecule has not undergone the activation process and is largely inactive [46].…”

Section: Discussionmentioning

confidence: 99%

Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs

et al. 2014

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The coupling of ER Ca2+-sensing STIM proteins and PM Orai Ca2+ entry channels generates “storeoperated” Ca2+ signals crucial in controlling responses in many cell types. The dimeric derivative of 2-aminoethoxydiphenyl borinate (2-APB), DPB162-AE, blocks functional coupling between STIM1 and Orai1 with an IC50 (200 nM) 100-fold lower than 2-APB. Unlike 2-APB, DPB162-AE does not affect L-type or TRPC channels or Ca2+ pumps at maximal STIM1-Orai1 blocking levels. DPB162-AE blocks STIM1-induced Orai1 or Orai2, but does not block Orai3 or STIM2-mediated effects. We narrowed the DPB162-AE site of action to the STIM-Orai activating region (SOAR) of STIM1. DPB162-AE does not prevent the SOAR-Orai1 interaction but potently blocks SOAR-mediated Orai1 channel activation, yet its action is not as an Orai1 channel pore blocker. Using the SOAR-F394H mutant which prevents both physical and functional coupling to Orai1, we reveal DPB162-AE rapidly restores SOAR-Orai binding but only slowly restores Orai1 channel-mediated Ca2+ entry. With the same SOAR mutant, 2-APB induces rapid physical and functional coupling to Orai1, but channel activation is transient. We infer that the actions of both 2-APB and DPB162-AE are directed toward the STIM1-Orai1 coupling interface. Compared to 2-APB, DPB162-AE is a much more potent and specific STIM1/Orai1 functional uncoupler. DPB162-AE provides an important pharmacological tool and a useful mechanistic probe for the function and coupling between STIM1 and Orai1 channels.

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Section: Discussionmentioning

confidence: 99%

Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs

et al. 2014

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“…An indication of coupling between STIM1 binding at the CBD and the channel gate was obtained recently from the effect of AnCoA4, a new Orai1 channel inhibitor, which binds only to the C terminus of Orai1 and inhibits channels made constitutively active by the TM1 mutation V102C [51]. But how is CAD-CBD interaction transmitted to the channel gate?…”

Section: Tm4 Regulates Orai1 Gatingmentioning

confidence: 99%

Critical role for Orai1 C-terminal domain and TM4 in CRAC channel gating

2015

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Calcium flux through store-operated calcium entry is a major regulator of intracellular calcium homeostasis and various calcium signaling pathways. Two key components of the store-operated calcium release-activated calcium channel are the Ca 2+-sensing protein stromal interaction molecule 1 (STIM1) and the channel pore-forming protein Orai1. Following calcium depletion from the endoplasmic reticulum, STIM1 undergoes conformational changes that unmask an Orai1-activating domain called CAD. CAD binds to two sites in Orai1, one in the N terminal and one in the C terminal. Most previous studies suggested that gating is initiated by STIM1 binding at the Orai1 N-terminal site, just proximal to the TM1 pore-lining segment, and that binding at the C terminal simply anchors STIM1 within reach of the N terminal. However, a recent study had challenged this view and suggested that the Orai1 C-terminal region is more than a simple STIM1-anchoring site. In this study, we establish that the Orai1 C-terminal domain plays a direct role in gating. We identify a linker region between TM4 and the C-terminal STIM1-binding segment of Orai1 as a key determinant that couples STIM1 binding to gating. We further find that Proline 245 in TM4 of Orai1 is essential for stabilizing the closed state of the channel. Taken together with previous studies, our results suggest a dual-trigger mechanism of Orai1 activation in which binding of STIM1 at the N-and C-terminal domains of Orai1 induces rearrangements in proximal membrane segments to open the channel.

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“…Channel gating depends on a direct interaction of Orai1 channels with STIM (reviewed extensively in Gudlur et al 2013). The initial interaction in cells that recruits Orai to junctions requires the C-terminal cytoplasmic regions of Orai (Li et al 2007).…”

Section: 7 Channel Gatingmentioning

confidence: 99%

The STIM-Orai Pathway: Orai, the Pore-Forming Subunit of the CRAC Channel

Gudlur

Hogan

2017

Advances in Experimental Medicine and Biology

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This chapter focuses on the Orai proteins, Orai1–Orai3, with special emphasis on Orai1, in humans and other mammals, and on the definitive evidence that Orai is the pore subunit of the CRAC channel. It begins by reviewing briefly the defining characteristics of the CRAC channel, then discusses the studies that implicated Orai as part of the store-operated Ca2+ entry pathway and as the CRAC channel pore subunit, and finally examines ongoing work that is providing insights into CRAC channel structure and gating.

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STIM–ORAI Interactions That Control the CRAC Channel

Cited by 42 publications

References 70 publications

Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs

Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs

Critical role for Orai1 C-terminal domain and TM4 in CRAC channel gating

The STIM-Orai Pathway: Orai, the Pore-Forming Subunit of the CRAC Channel

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