The Orai Pore Opening Mechanism
Abstract
:1. Introduction
1.1. The Ca2+ Ion—A Versatile Second Messenger
1.2. Overview of the Activation Cascade of the CRAC Entry
2. Functional and Structural Properties of Orai1 Channel Activation and Stoichiometric Requirements
2.1. Biophysical Features and Authentic Hallmarks of CRAC Channels
2.2. Structural Features of Orai Proteins
2.3. Crucial STIM1-Binding Sites within Orai1
2.4. Stoichiometry of STIM1 for Orai1 Activation
3. Dynamics within the Orai Channel Complex upon Pore Opening
3.1. The Orai1 Pore
3.2. Orai Gating Necessitates Several Checkpoint Residues in All TM Domains to Be Intact
Orai1 | Location | GoF | LoF/LoFweak | Disease | Reference |
---|---|---|---|---|---|
R83 | N-term. (CETR) | R83A | [41,82] | ||
K85 | N-term. (CETR) | K85E | [41,82] | ||
S89 | N-term. (CETR) | [92] | |||
S90 | N-term. (CETR) | [92] | |||
R91 | TM1 (MTR) | R91W (dOrai K163W) | Immunodeficiencies | [7,92] | |
S93 | TM1 (MTR) | [39] | |||
L96 | TM1 (MTR) | [39] | |||
S97 | TM1 (MTR) | S97C | Stormorken-like syndrome | [39,93] | |
S97M/L/I/V | [39] | ||||
G98 | TM1 (MTR) | G98S | Tubular aggregate myopathy | [94,95] | |
G98R | Immunodeficiencies | [96] | |||
F99 | TM1 (MTR) | F99Y/M/S/T/W/C/G | [88] | ||
M101 | TM1 (MTR) | M101F | [39,89,97] | ||
V102 | TM1 (MTR) | V102A/C/G/S/T | V102D/W | [63] | |
A103 | TM1 (MTR) | A103E | Immunodeficiencies | [98] | |
M104 | TM1 (MTR) | [39] | |||
V107 | TM1 (MTR) | V107M | Tubular aggregate myopathy | [99] | |
H134 | TM2 (MTR) | H134A/C/S/T (dOrai H206A) | H134W | [36,39,44,82] | |
F136 | TM2 (MTR) | F136A/S | [82] | ||
A137 | TM2 (MTR) | A137V | Colorectal tumor | [44,82] | |
L138 | TM2 (MTR) | L138F | Tubular aggregate myopathy | [44] | |
M139 | TM2 (MTR) | M139V | Stomach carcinoma | [44] | |
S141 | TM2 (MTR) | S141C | [39] | ||
T142 | TM2 (MTR) | T142C | [82] | ||
E149 | loop2 (CETR) | E149K/R | [41,82] | ||
S159 | loop2 (CETR) | S159L | [44] | ||
E166 | loop2 (CETR) | [43,81] | |||
E173 | TM3 (CETR) | E173K | [41,81,82] | ||
L174 | TM3 (CETR) | L174D/K | [78,82] | ||
A175 | TM3 (CETR) | A175D/K | [78] | ||
W176 | W176A/C/S | [54,82,100] | |||
V181 | TM3 (MTR) | V181A/C/S | [54,82] | ||
V181SfsX8 | Autoimmunity, ectodermal dysplasia | [96] | |||
G183 | G183D | Glioblastoma | [44] | ||
T184 | TM3 (MTR) | T184M | Tubular aggregate myopathy | [99] | |
L185 | TM3 (MTR) | L185A (Orai3 F160A), L185C/S | [54] | ||
F187 | TM3 (MTR) | F187A/C/S | [34,39,82] | ||
L188 | TM3 (MTR) | L188S | [82] | ||
E190 | TM3 (MTR) | E160Q | [101] | ||
V191 | TM3 (MTR) | [39,82] | |||
L194 | TM3 (MTR) | L194S/N | [39,82] | ||
L194P | Autoimmunity, ectodermal dysplasia | [96] | |||
A235 | TM4 (MTR) | A235C | A235W | [39,82] | |
S239 | TM4 (MTR) | S239C | S239W | [39,82] | |
M243 | TM4 (MTR) | M243S | [82] | ||
P245 | TM4 (MTR) | P245X (X = any canonical aa); (dOrai P288L), | Stormorken-like syndrome | [5,34,39,82,102] | |
G247 | TM4 (MTR) | G247S | [44] | ||
F250 | TM4 (MTR) | F250A/C/S | [39,54,82] | ||
L261 | TM4 (CETR) | L261A/C/S | L261D/K | [78,82] | |
261LVSHK265 | TM4 ext | ANSGA | [78] | ||
V262 | TM4 ext | V262N | [82] | ||
L273 | C-term. | L273D/S | [26,72,74,85,102] | ||
L276 | C-term. | L276D/S | [26,72,74,85,102] |
3.3. Global Conformational Changes within the Orai Complex Are Indispensable for Pore Opening
3.4. Pathophysiological Roles of Orai1 GoF and LoF Mutants
4. Essential Orai Gating Checkpoints
4.1. Gating Checkpoints in the MTR
4.1.1. MTR of TM2/TM3
4.1.2. The Hydrophobic Cluster at the TM1–TM2/3 Ring Interface
4.1.3. Kink in TM4 and Outer TM4 Segment
4.2. Gating Checkpoints in the CETR
4.2.1. The Major Role of the Orai1 Hinge Region in CRAC Channel Activation
4.2.2. Hinge Plate—The Hydrophobic Interface of TM3–TM4 Critical in Gating
4.2.3. Communication between N-Terminus and Loop2 Established by Cytosolic Triangles
4.3. Gating Regions Spanning from the MTR to the CETR
4.3.1. TM2/3 Ring Boost Cooperativity in STIM1-Mediated Orai1 Activation
4.3.2. Serine Ridge at the Intersection of TM1 and the TM2/TM3 Ring
5. Isoform-Specific Orai Gating
6. Summary, Open Questions, and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
2-APB | 2-aminoethoxydiphenyl borate |
Å | angstrom (unit of length equal to 10−10 m) |
aa | amino acid |
ANSGA | four-point mutation in hinge region aa position 261–265 |
Ca2+ | calcium ion |
CAD | Ca2+ release-activated Ca2+-activating domain |
CAR | Ca2+-accumulating region |
CC | coiled-coil |
cCAD | Caenorhabditis elegans CAD |
CETR | cytosolic extended transmembrane region |
cOrai | Caenorhabditis elegans Orai |
CRAC | Ca2+ release-activated Ca2+ |
cryo-EM | cryogenic electron microscopy |
Cs+ | cesium ion |
C-term | C-terminus |
cSTIM | Caenorhabditis elegans STIM |
∆N | represents N terminal deletion mutants |
dOrai | Drosophila melanogaster Orai |
DVF | divalent-free |
ER | endoplasmic reticulum |
ETON | extended transmembrane Orai1 N-terminal |
FCDI | fast calcium-dependent inactivation |
FIRE | FRET-derived interaction in a restricted environment |
FRAP | fluorescence recovery after photobleaching |
FRET | fluorescence resonance energy transfer |
GoF | gain of function |
ICa2+ | CRAC current |
INa+ | sodium current in sodium divalent-free solution |
ID | inhibitory domain |
IP3 | inositol triphosphate |
L-type | long-lasting calcium channel |
LoF | loss of function |
LV(SHK) | hinge region aa position 261–265 |
MD | molecular dynamics simulations |
MTR | middle transmembrane region |
Na+-DVF | sodium divalent free |
nEF | noncanonical EF hand |
NMR | nuclear magnetic resonance |
N-term | N-terminus |
OASF | Orai-activating small fragment |
Orai 1–3 | Orai proteins (also O1–3) |
PBD | polybasic domain |
PIP2 | phosphatidylinositol 4,5-bisphosphate |
PM | plasma membrane |
SAM | sterile α-motif |
S | signal peptide |
SCDI | slow calcium-dependent inactivation |
SOAR | STIM–Orai-activating region |
SOCE | store-operated calcium entry |
STIM | stromal interaction molecule |
TAM | tubular aggregate myopathy |
TM | transmembrane helices |
TRP | transient receptor potential ion channel (C-canonical, M-melastatin, V-vallinoid) |
References
- Berridge, M.J. The Inositol Trisphosphate/Calcium Signaling Pathway in Health and Disease. Physiol. Rev. 2016, 96, 1261–1296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Parekh, A.B.; Putney, J.W., Jr. Store-operated calcium channels. Physiol. Rev. 2005, 85, 757–810. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Prakriya, M.; Lewis, R.S. Store-Operated Calcium Channels. Physiol. Rev. 2015, 95, 1383–1436. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Morin, G.; Bruechle, N.O.; Singh, A.R.; Knopp, C.; Jedraszak, G.; Elbracht, M.; Bremond-Gignac, D.; Hartmann, K.; Sevestre, H.; Deutz, P.; et al. Gain-of-Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome. Hum. Mutat. 2014, 35, 1221–1232. [Google Scholar] [CrossRef]
- Nesin, V.; Wiley, G.; Kousi, M.; Ong, E.C.; Lehmann, T.; Nicholl, D.J.; Suri, M.; Shahrizaila, N.; Katsanis, N.; Gaffney, P.M.; et al. Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proc. Natl. Acad. Sci. USA 2014, 111, 4197–4202. [Google Scholar] [CrossRef] [Green Version]
- Thompson, J.L.; Mignen, O.; Shuttleworth, T.J. The Orai1 severe combined immune deficiency mutation and calcium release-activated Ca2+ channel function in the heterozygous condition. J. Biol. Chem. 2009, 284, 6620–6626. [Google Scholar] [CrossRef] [Green Version]
- Feske, S.; Gwack, Y.; Prakriya, M.; Srikanth, S.; Puppel, S.H.; Tanasa, B.; Hogan, P.G.; Lewis, R.S.; Daly, M.; Rao, A. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 2006, 441, 179–185. [Google Scholar] [CrossRef]
- Lacruz, R.S.; Feske, S. Diseases caused by mutations in ORAI1 and STIM1. Ann. N. Y. Acad. Sci. 2015, 1356, 45–79. [Google Scholar] [CrossRef] [Green Version]
- Hewavitharana, T.; Deng, X.; Soboloff, J.; Gill, D.L. Role of STIM and Orai proteins in the store-operated calcium signaling pathway. Cell Calcium 2007, 42, 173–182. [Google Scholar] [CrossRef]
- Zhang, S.L.; Yu, Y.; Roos, J.; Kozak, J.A.; Deerinck, T.J.; Ellisman, M.H.; Stauderman, K.A.; Cahalan, M.D. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 2005, 437, 902–905. [Google Scholar] [CrossRef]
- Zhang, S.L.; Yeromin, A.V.; Zhang, X.H.; Yu, Y.; Safrina, O.; Penna, A.; Roos, J.; Stauderman, K.A.; Cahalan, M.D. Genome-wide RNAi screen of Ca(2+) influx identifies genes that regulate Ca(2+) release-activated Ca(2+) channel activity. Proc. Natl. Acad. Sci. USA 2006, 103, 9357–9362. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gudlur, A.; Zeraik, A.E.; Hirve, N.; Rajanikanth, V.; Bobkov, A.A.; Ma, G.; Zheng, S.; Wang, Y.; Zhou, Y.; Komives, E.A.; et al. Calcium sensing by the STIM1 ER-luminal domain. Nat. Commun. 2018, 9, 4536. [Google Scholar] [CrossRef] [PubMed]
- Schober, R.; Bonhenry, D.; Lunz, V.; Zhu, J.; Krizova, A.; Frischauf, I.; Fahrner, M.; Zhang, M.; Waldherr, L.; Schmidt, T.; et al. Sequential activation of STIM1 links Ca(2+) with luminal domain unfolding. Sci. Signal. 2019, 12. [Google Scholar] [CrossRef] [PubMed]
- Sallinger, M.; Tiffner, A.; Schmidt, T.; Bonhenry, D.; Waldherr, L.; Frischauf, I.; Lunz, V.; Derler, I.; Schober, R.; Schindl, R. Luminal STIM1 Mutants that Cause Tubular Aggregate Myopathy Promote Autophagic Processes. Int. J. Mol. Sci. 2020, 21, 4410. [Google Scholar] [CrossRef] [PubMed]
- Fahrner, M.; Muik, M.; Schindl, R.; Butorac, C.; Stathopulos, P.; Zheng, L.; Jardin, I.; Ikura, M.; Romanin, C. A coiled-coil clamp controls both conformation and clustering of stromal interaction molecule 1 (STIM1). J. Biol. Chem. 2014, 289, 33231–33244. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zheng, L.; Stathopulos, P.B.; Schindl, R.; Li, G.Y.; Romanin, C.; Ikura, M. Auto-inhibitory role of the EF-SAM domain of STIM proteins in store-operated calcium entry. Proc. Natl. Acad. Sci. USA 2011, 108, 1337–1342. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hirve, N.; Rajanikanth, V.; Hogan, P.G.; Gudlur, A. Coiled-Coil Formation Conveys a STIM1 Signal from ER Lumen to Cytoplasm. Cell Rep. 2018, 22, 72–83. [Google Scholar] [CrossRef] [Green Version]
- Ma, G.; Wei, M.; He, L.; Liu, C.; Wu, B.; Zhang, S.L.; Jing, J.; Liang, X.; Senes, A.; Tan, P.; et al. Inside-out Ca(2+) signalling prompted by STIM1 conformational switch. Nat. Commun. 2015, 6, 7826. [Google Scholar] [CrossRef] [Green Version]
- Muik, M.; Fahrner, M.; Derler, I.; Schindl, R.; Bergsmann, J.; Frischauf, I.; Groschner, K.; Romanin, C. A Cytosolic Homomerization and a Modulatory Domain within STIM1 C Terminus Determine Coupling to ORAI1 Channels. J. Biol. Chem. 2009, 284, 8421–8426. [Google Scholar] [CrossRef] [Green Version]
- Liou, J.; Kim, M.L.; Heo, W.D.; Jones, J.T.; Myers, J.W.; Ferrell, J.E., Jr.; Meyer, T. STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr. Biol. 2005, 15, 1235–1241. [Google Scholar] [CrossRef] [Green Version]
- Yuan, J.P.; Zeng, W.; Dorwart, M.R.; Choi, Y.J.; Worley, P.F.; Muallem, S. SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat. Cell Biol. 2009, 11, 337–343. [Google Scholar] [CrossRef]
- Park, C.Y.; Hoover, P.J.; Mullins, F.M.; Bachhawat, P.; Covington, E.D.; Raunser, S.; Walz, T.; Garcia, K.C.; Dolmetsch, R.E.; Lewis, R.S. STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 2009, 136, 876–890. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mullins, F.M.; Lewis, R.S. The inactivation domain of STIM1 is functionally coupled with the Orai1 pore to enable Ca2+-dependent inactivation. J. Gen. Physiol. 2016, 147, 153–164. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Derler, I.; Fahrner, M.; Muik, M.; Lackner, B.; Schindl, R.; Groschner, K.; Romanin, C. A Ca2(+) release-activated Ca2(+) (CRAC) modulatory domain (CMD) within STIM1 mediates fast Ca2(+)-dependent inactivation of ORAI1 channels. J. Biol. Chem. 2009, 284, 24933–24938. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ercan, E.; Momburg, F.; Engel, U.; Temmerman, K.; Nickel, W.; Seedorf, M. A conserved, lipid-mediated sorting mechanism of yeast Ist2 and mammalian STIM proteins to the peripheral ER. Traffic 2009, 10, 1802–1818. [Google Scholar] [CrossRef]
- Frischauf, I.; Muik, M.; Derler, I.; Bergsmann, J.; Fahrner, M.; Schindl, R.; Groschner, K.; Romanin, C. Molecular determinants of the coupling between STIM1 and Orai channels: Differential activation of Orai1-3 channels by a STIM1 coiled-coil mutant. J. Biol. Chem. 2009, 284, 21696–21706. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, X.; Wang, Y.; Zhou, Y.; Hendron, E.; Mancarella, S.; Andrake, M.D.; Rothberg, B.S.; Soboloff, J.; Gill, D.L. Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site. Nat. Commun. 2014, 5, 3183. [Google Scholar] [CrossRef]
- Zhou, Y.; Cai, X.; Nwokonko, R.M.; Loktionova, N.A.; Wang, Y.; Gill, D.L. The STIM-Orai coupling interface and gating of the Orai1 channel. Cell Calcium 2017, 63, 8–13. [Google Scholar] [CrossRef] [Green Version]
- Derler, I.; Jardin, I.; Romanin, C. Molecular mechanisms of STIM/Orai communication. Am. J. Physiol. Cell Physiol. 2016, 310, C643–C662. [Google Scholar] [CrossRef] [Green Version]
- Yeung, P.S.; Yamashita, M.; Prakriya, M. Molecular basis of allosteric Orai1 channel activation by STIM1. J. Physiol. 2020, 598, 1707–1723. [Google Scholar] [CrossRef]
- Yeung, P.S.; Prakriya, M. The exquisitely cooperative nature of Orai1 channel activation. J. Gen. Physiol. 2018, 150, 1352–1355. [Google Scholar] [CrossRef] [PubMed]
- Butorac, C.; Krizova, A.; Derler, I. Review: Structure and Activation Mechanisms of CRAC Channels. Adv. Exp. Med. Biol. 2020, 1131, 547–604. [Google Scholar] [PubMed]
- Krizova, A.; Maltan, L.; Derler, I. Critical parameters maintaining authentic CRAC channel hallmarks. Eur. Biophys. J. 2019, 48, 425–445. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, X.; Wu, G.; Yu, Y.; Chen, X.; Ji, R.; Lu, J.; Li, X.; Zhang, X.; Yang, X.; Shen, Y. Molecular understanding of calcium permeation through the open Orai channel. PLoS Biol. 2019, 17, e3000096. [Google Scholar] [CrossRef]
- Hou, X.; Pedi, L.; Diver, M.M.; Long, S.B. Crystal structure of the calcium release-activated calcium channel Orai. Science 2012, 338, 1308–1313. [Google Scholar] [CrossRef] [Green Version]
- Hou, X.; Burstein, S.R.; Long, S.B. Structures reveal opening of the store-operated calcium channel Orai. eLife 2018, 7. [Google Scholar] [CrossRef]
- Yamashita, M.; Ing, C.E.; Yeung, P.S.; Maneshi, M.M.; Pomes, R.; Prakriya, M. The basic residues in the Orai1 channel inner pore promote opening of the outer hydrophobic gate. J. Gen. Physiol. 2020, 152. [Google Scholar] [CrossRef]
- Alavizargar, A.; Berti, C.; Ejtehadi, M.R.; Furini, S. Molecular Dynamics Simulations of Orai Reveal How the Third Transmembrane Segment Contributes to Hydration and Ca (2+) Selectivity in Calcium Release-Activated Calcium Channels. J. Phys. Chem. B 2018, 122, 4407–4417. [Google Scholar] [CrossRef]
- Yeung, P.S.; Yamashita, M.; Ing, C.E.; Pomes, R.; Freymann, D.M.; Prakriya, M. Mapping the functional anatomy of Orai1 transmembrane domains for CRAC channel gating. Proc. Natl. Acad. Sci. USA 2018, 115, E5193–E5202. [Google Scholar] [CrossRef] [Green Version]
- Ma, G.; He, L.; Liu, S.; Xie, J.; Huang, Z.; Jing, J.; Lee, Y.T.; Wang, R.; Luo, H.; Han, W.; et al. Optogenetic engineering to probe the molecular choreography of STIM1-mediated cell signaling. Nat. Commun. 2020, 11, 1039. [Google Scholar] [CrossRef]
- Dong, H.; Zhang, Y.; Song, R.; Xu, J.; Yuan, Y.; Liu, J.; Li, J.; Zheng, S.; Liu, T.; Lu, B.; et al. Toward a Model for Activation of Orai Channel. iScience 2019, 16, 356–367. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dong, H.; Fiorin, G.; Carnevale, V.; Treptow, W.; Klein, M.L. Pore waters regulate ion permeation in a calcium release-activated calcium channel. Proc. Natl. Acad. Sci. USA 2013, 110, 17332–17337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fahrner, M.; Pandey, S.K.; Muik, M.; Traxler, L.; Butorac, C.; Stadlbauer, M.; Zayats, V.; Krizova, A.; Plenk, P.; Frischauf, I.; et al. Communication between N terminus and loop2 tunes Orai activation. J. Biol. Chem. 2018, 293, 1271–1285. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Frischauf, I.; Litvinukova, M.; Schober, R.; Zayats, V.; Svobodova, B.; Bonhenry, D.; Lunz, V.; Cappello, S.; Tociu, L.; Reha, D.; et al. Transmembrane helix connectivity in Orai1 controls two gates for calcium-dependent transcription. Sci. Signal. 2017, 10. [Google Scholar] [CrossRef] [Green Version]
- Frischauf, I.; Zayats, V.; Deix, M.; Hochreiter, A.; Jardin, I.; Muik, M.; Lackner, B.; Svobodova, B.; Pammer, T.; Litvinukova, M.; et al. A calcium-accumulating region, CAR, in the channel Orai1 enhances Ca2+ permeation and SOCE-induced gene transcription. Sci. Signal. 2015, 8, ra131. [Google Scholar] [CrossRef] [Green Version]
- Novello, M.J.; Zhu, J.; Feng, Q.; Ikura, M.; Stathopulos, P.B. Structural elements of stromal interaction molecule function. Cell Calcium 2018, 73, 88–94. [Google Scholar] [CrossRef]
- Stathopulos, P.B.; Ikura, M. Structure and function of endoplasmic reticulum STIM calcium sensors. Curr. Top. Membr. 2013, 71, 59–93. [Google Scholar]
- Stathopulos, P.B.; Zheng, L.; Li, G.Y.; Plevin, M.J.; Ikura, M. Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell 2008, 135, 110–122. [Google Scholar] [CrossRef] [Green Version]
- Stathopulos, P.B.; Li, G.Y.; Plevin, M.J.; Ames, J.B.; Ikura, M. Stored Ca2+ depletion-induced oligomerization of stromal interaction molecule 1 (STIM1) via the EF-SAM region: An initiation mechanism for capacitive Ca2+ entry. J. Biol. Chem. 2006, 281, 35855–35862. [Google Scholar] [CrossRef] [Green Version]
- Yang, X.; Jin, H.; Cai, X.; Li, S.; Shen, Y. Structural and mechanistic insights into the activation of Stromal interaction molecule 1 (STIM1). Proc. Natl. Acad. Sci. USA 2012, 109, 5657–5662. [Google Scholar] [CrossRef] [Green Version]
- Hou, X.; Outhwaite, I.R.; Pedi, L.; Long, S.B. Cryo-EM structure of the calcium release-activated calcium channel Orai in an open conformation. eLife 2020, 9. [Google Scholar] [CrossRef] [PubMed]
- Hogan, P.G.; Rao, A. Store-operated calcium entry: Mechanisms and modulation. Biochem. Biophys. Res. Commun. 2015, 460, 40–49. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Prakriya, M.; Lewis, R.S. Regulation of CRAC channel activity by recruitment of silent channels to a high open-probability gating mode. J. Gen. Physiol. 2006, 128, 373–386. [Google Scholar] [CrossRef] [PubMed]
- Derler, I.; Butorac, C.; Krizova, A.; Stadlbauer, M.; Muik, M.; Fahrner, M.; Frischauf, I.; Romanin, C. Authentic CRAC channel activity requires STIM1 and the conserved portion of the Orai N terminus. J. Biol. Chem. 2018, 293, 1259–1270. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hoth, M.; Penner, R. Calcium release-activated calcium current in rat mast cells. J. Physiol. 1993, 465, 359–386. [Google Scholar] [CrossRef] [PubMed]
- Hoth, M. Calcium and barium permeation through calcium release-activated calcium (CRAC) channels. Pflugers Arch. 1995, 430, 315–322. [Google Scholar] [CrossRef] [PubMed]
- Zweifach, A.; Lewis, R.S. Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores. Proc. Natl. Acad. Sci. USA 1993, 90, 6295–6299. [Google Scholar] [CrossRef] [Green Version]
- Lis, A.; Peinelt, C.; Beck, A.; Parvez, S.; Monteilh-Zoller, M.; Fleig, A.; Penner, R. CRACM1, CRACM2, and CRACM3 are store-operated Ca2+ channels with distinct functional properties. Curr. Biol. 2007, 17, 794–800. [Google Scholar] [CrossRef] [Green Version]
- Hoth, M.; Penner, R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 1992, 355, 353–356. [Google Scholar] [CrossRef]
- Lepple-Wienhues, A.; Cahalan, M.D. Conductance and permeation of monovalent cations through depletion-activated Ca2+ channels (ICRAC) in Jurkat T cells. Biophys. J. 1996, 71, 787–794. [Google Scholar] [CrossRef] [Green Version]
- Cataldi, M.; Perez-Reyes, E.; Tsien, R.W. Differences in apparent pore sizes of low and high voltage-activated Ca2+ channels. J. Biol. Chem. 2002, 277, 45969–45976. [Google Scholar] [CrossRef] [Green Version]
- Saotome, K.; Singh, A.K.; Yelshanskaya, M.V.; Sobolevsky, A.I. Crystal structure of the epithelial calcium channel TRPV6. Nature 2016, 534, 506–511. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McNally, B.A.; Somasundaram, A.; Yamashita, M.; Prakriya, M. Gated regulation of CRAC channel ion selectivity by STIM1. Nature 2012, 482, 241–245. [Google Scholar] [CrossRef] [PubMed]
- Derler, I.; Plenk, P.; Fahrner, M.; Muik, M.; Jardin, I.; Schindl, R.; Gruber, H.J.; Groschner, K.; Romanin, C. The extended transmembrane Orai1 N-terminal (ETON) region combines binding interface and gate for Orai1 activation by STIM1. J. Biol. Chem. 2013, 288, 29025–29034. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zweifach, A.; Lewis, R.S. Rapid inactivation of depletion-activated calcium current (ICRAC) due to local calcium feedback. J. Gen. Physiol. 1995, 105, 209–226. [Google Scholar] [CrossRef] [Green Version]
- Schindl, R.; Frischauf, I.; Bergsmann, J.; Muik, M.; Derler, I.; Lackner, B.; Groschner, K.; Romanin, C. Plasticity in Ca2+ selectivity of Orai1/Orai3 heteromeric channel. Proc. Natl. Acad. Sci. USA 2009, 106, 19623–19628. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Scrimgeour, N.R.; Wilson, D.P.; Barritt, G.J.; Rychkov, G.Y. Structural and stoichiometric determinants of Ca2+ release-activated Ca2+ (CRAC) channel Ca2+-dependent inactivation. Biochim. Biophys. Acta 2014, 1838, 1281–1287. [Google Scholar] [CrossRef] [Green Version]
- Scrimgeour, N.; Litjens, T.; Ma, L.; Barritt, G.J.; Rychkov, G.Y. Properties of Orai1 mediated store-operated current depend on the expression levels of STIM1 and Orai1 proteins. J. Physiol. 2009, 587, 2903–2918. [Google Scholar] [CrossRef]
- Albarran, L.; Lopez, J.J.; Jardin, I.; Sanchez-Collado, J.; Berna-Erro, A.; Smani, T.; Camello, P.J.; Salido, G.M.; Rosado, J.A. EFHB is a Novel Cytosolic Ca2+ Sensor That Modulates STIM1-SARAF Interaction. Cell Physiol. Biochem. 2018, 51, 1164–1178. [Google Scholar] [CrossRef]
- Jha, A.; Ahuja, M.; Maleth, J.; Moreno, C.M.; Yuan, J.P.; Kim, M.S.; Muallem, S. The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function. J. Cell Biol. 2013, 202, 71–79. [Google Scholar] [CrossRef] [Green Version]
- Zhou, Y.; Nwokonko, R.M.; Baraniak, J.H., Jr.; Trebak, M.; Lee, K.P.K.; Gill, D.L. The remote allosteric control of Orai channel gating. PLoS Biol. 2019, 17, e3000413. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Muik, M.; Frischauf, I.; Derler, I.; Fahrner, M.; Bergsmann, J.; Eder, P.; Schindl, R.; Hesch, C.; Polzinger, B.; Fritsch, R.; et al. Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation. J. Biol. Chem. 2008, 283, 8014–8022. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, Z.; Lu, J.; Xu, P.; Xie, X.; Chen, L.; Xu, T. Mapping the interacting domains of STIM1 and Orai1 in Ca2+ release-activated Ca2+ channel activation. J. Biol. Chem. 2007, 282, 29448–29456. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McNally, B.A.; Somasundaram, A.; Jairaman, A.; Yamashita, M.; Prakriya, M. The C- and N-terminal STIM1 binding sites on Orai1 are required for both trapping and gating CRAC channels. J. Physiol. 2013, 591, 2833–2850. [Google Scholar] [CrossRef] [PubMed]
- Navarro-Borelly, L.; Somasundaram, A.; Yamashita, M.; Ren, D.; Miller, R.J.; Prakriya, M. STIM1-Orai1 interactions and Orai1 conformational changes revealed by live-cell FRET microscopy. J. Physiol. 2008, 586, 5383–5401. [Google Scholar] [CrossRef]
- Palty, R.; Isacoff, E.Y. Cooperative Binding of Stromal Interaction Molecule 1 (STIM1) to the N and C Termini of Calcium Release-activated Calcium Modulator 1 (Orai1). J. Biol. Chem. 2016, 291, 334–341. [Google Scholar] [CrossRef] [Green Version]
- Stathopulos, P.B.; Schindl, R.; Fahrner, M.; Zheng, L.; Gasmi-Seabrook, G.M.; Muik, M.; Romanin, C.; Ikura, M. STIM1/Orai1 coiled-coil interplay in the regulation of store-operated calcium entry. Nat. Commun. 2013, 4, 2963. [Google Scholar] [CrossRef]
- Zhou, Y.; Cai, X.; Loktionova, N.A.; Wang, X.; Nwokonko, R.M.; Wang, X.; Wang, Y.; Rothberg, B.S.; Trebak, M.; Gill, D.L. The STIM1-binding site nexus remotely controls Orai1 channel gating. Nat. Commun. 2016, 7, 13725. [Google Scholar] [CrossRef] [Green Version]
- Niu, L.; Wu, F.; Li, K.; Li, J.; Zhang, S.L.; Hu, J.; Wang, Q. STIM1 interacts with termini of Orai channels in a sequential manner. J. Cell Sci. 2020, 133, jcs239491. [Google Scholar] [CrossRef]
- Zhou, Y.; Meraner, P.; Kwon, H.T.; Machnes, D.; Oh-hora, M.; Zimmer, J.; Huang, Y.; Stura, A.; Rao, A.; Hogan, P.G. STIM1 gates the store-operated calcium channel ORAI1 in vitro. Nat. Struct. Mol. Biol. 2010, 17, 112–116. [Google Scholar] [CrossRef] [Green Version]
- Butorac, C.; Muik, M.; Derler, I.; Stadlbauer, M.; Lunz, V.; Krizova, A.; Lindinger, S.; Schober, R.; Frischauf, I.; Bhardwaj, R.; et al. A novel STIM1-Orai1 gating interface essential for CRAC channel activation. Cell Calcium 2019, 79, 57–67. [Google Scholar] [CrossRef]
- Tiffner, A.; Schober, R.; Höglinger, C.; Bonhenry, D.; Pandey, S.; Lunz, V.; Sallinger, M.; Frischauf, I.; Fahrner, M.; Lindinger, S.; et al. A series of Orai1 gating checkpoints in transmembrane and cytosolic regions requires clearance for CRAC channel opening. J. Biol. Chem. 2020. [Google Scholar] [CrossRef] [PubMed]
- Yen, M.; Lokteva, L.A.; Lewis, R.S. Functional Analysis of Orai1 Concatemers Supports a Hexameric Stoichiometry for the CRAC Channel. Biophys. J. 2016, 111, 1897–1907. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hoover, P.J.; Lewis, R.S. Stoichiometric requirements for trapping and gating of Ca2+ release-activated Ca2+ (CRAC) channels by stromal interaction molecule 1 (STIM1). Proc. Natl. Acad. Sci. USA 2011, 108, 13299–13304. [Google Scholar] [CrossRef] [Green Version]
- Li, Z.; Liu, L.; Deng, Y.; Ji, W.; Du, W.; Xu, P.; Chen, L.; Xu, T. Graded activation of CRAC channel by binding of different numbers of STIM1 to Orai1 subunits. Cell Res. 2011, 21, 305–315. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Palty, R.; Fu, Z.; Isacoff, E.Y. Sequential Steps of CRAC Channel Activation. Cell Rep. 2017, 19, 1929–1939. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yen, M.; Lewis, R.S. Physiological CRAC channel activation and pore properties require STIM1 binding to all six Orai1 subunits. J. Gen. Physiol. 2018, 150, 1373–1385. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yamashita, M.; Yeung, P.S.; Ing, C.E.; McNally, B.A.; Pomes, R.; Prakriya, M. STIM1 activates CRAC channels through rotation of the pore helix to open a hydrophobic gate. Nat. Commun. 2017, 8, 14512. [Google Scholar] [CrossRef] [Green Version]
- McNally, B.A.; Yamashita, M.; Engh, A.; Prakriya, M. Structural determinants of ion permeation in CRAC channels. Proc. Natl. Acad. Sci. USA 2009, 106, 22516–22521. [Google Scholar] [CrossRef] [Green Version]
- Zhou, Y.; Ramachandran, S.; Oh-Hora, M.; Rao, A.; Hogan, P.G. Pore architecture of the ORAI1 store-operated calcium channel. Proc. Natl. Acad. Sci. USA 2010, 107, 4896–4901. [Google Scholar] [CrossRef] [Green Version]
- Yamashita, M.; Navarro-Borelly, L.; McNally, B.A.; Prakriya, M. Orai1 mutations alter ion permeation and Ca2+-dependent fast inactivation of CRAC channels: Evidence for coupling of permeation and gating. J. Gen. Physiol. 2007, 130, 525–540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Derler, I.; Fahrner, M.; Carugo, O.; Muik, M.; Bergsmann, J.; Schindl, R.; Frischauf, I.; Eshaghi, S.; Romanin, C. Increased hydrophobicity at the N terminus/membrane interface impairs gating of the severe combined immunodeficiency-related ORAI1 mutant. J. Biol. Chem. 2009, 284, 15903–15915. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Garibaldi, M.; Fattori, F.; Riva, B.; Labasse, C.; Brochier, G.; Ottaviani, P.; Sacconi, S.; Vizzaccaro, E.; Laschena, F.; Romero, N.B.; et al. A novel gain-of-function mutation in ORAI1 causes late-onset tubular aggregate myopathy and congenital miosis. Clin. Genet. 2017, 91, 780–786. [Google Scholar] [CrossRef]
- Bulla, M.; Gyimesi, G.; Kim, J.H.; Bhardwaj, R.; Hediger, M.A.; Frieden, M.; Demaurex, N. ORAI1 channel gating and selectivity is differentially altered by natural mutations in the first or third transmembrane domain. J. Physiol. 2019, 597, 561–582. [Google Scholar] [CrossRef] [Green Version]
- Endo, Y.; Noguchi, S.; Hara, Y.; Hayashi, Y.K.; Motomura, K.; Miyatake, S.; Murakami, N.; Tanaka, S.; Yamashita, S.; Kizu, R.; et al. Dominant mutations in ORAI1 cause tubular aggregate myopathy with hypocalcemia via constitutive activation of store-operated Ca(2)(+) channels. Hum. Mol. Genet. 2015, 24, 637–648. [Google Scholar] [CrossRef] [Green Version]
- Lian, J.; Cuk, M.; Kahlfuss, S.; Kozhaya, L.; Vaeth, M.; Rieux-Laucat, F.; Picard, C.; Benson, M.J.; Jakovcevic, A.; Bilic, K.; et al. ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency. J. Allergy Clin. Immunol. 2018, 142, 1297–1310.e11. [Google Scholar] [CrossRef] [PubMed]
- Yeung, P.S.; Ing, C.E.; Yamashita, M.; Pomes, R.; Prakriya, M. A sulfur-aromatic gate latch is essential for opening of the Orai1 channel pore. eLife 2020, 9. [Google Scholar] [CrossRef] [PubMed]
- McCarl, C.A.; Picard, C.; Khalil, S.; Kawasaki, T.; Rother, J.; Papolos, A.; Kutok, J.; Hivroz, C.; Ledeist, F.; Plogmann, K.; et al. ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia. J. Allergy Clin. Immunol. 2009, 124, 1311–1318.e7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bohm, J.; Bulla, M.; Urquhart, J.E.; Malfatti, E.; Williams, S.G.; O’Sullivan, J.; Szlauer, A.; Koch, C.; Baranello, G.; Mora, M.; et al. ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy. Hum. Mutat. 2017, 38, 426–438. [Google Scholar] [CrossRef] [Green Version]
- Srikanth, S.; Yee, M.K.; Gwack, Y.; Ribalet, B. The third transmembrane segment of orai1 protein modulates Ca2+ release-activated Ca2+ (CRAC) channel gating and permeation properties. J. Biol Chem. 2011, 286, 35318–35328. [Google Scholar] [CrossRef] [Green Version]
- Prakriya, M.; Feske, S.; Gwack, Y.; Srikanth, S.; Rao, A.; Hogan, P.G. Orai1 is an essential pore subunit of the CRAC channel. Nature 2006, 443, 230–233. [Google Scholar] [CrossRef] [PubMed]
- Palty, R.; Stanley, C.; Isacoff, E.Y. Critical role for Orai1 C-terminal domain and TM4 in CRAC channel gating. Cell Res. 2015, 25, 963–980. [Google Scholar] [CrossRef] [Green Version]
- Zhang, S.L.; Yeromin, A.V.; Hu, J.; Amcheslavsky, A.; Zheng, H.; Cahalan, M.D. Mutations in Orai1 transmembrane segment 1 cause STIM1-independent activation of Orai1 channels at glycine 98 and channel closure at arginine 91. Proc. Natl. Acad. Sci. USA 2011, 108, 17838–17843. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cai, X.; Zhou, Y.; Nwokonko, R.M.; Loktionova, N.A.; Wang, X.; Xin, P.; Trebak, M.; Wang, Y.; Gill, D.L. The Orai1 Store-operated Calcium Channel Functions as a Hexamer. J. Biol. Chem. 2016, 291, 25764–25775. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tirado-Lee, L.; Yamashita, M.; Prakriya, M. Conformational Changes in the Orai1 C-Terminus Evoked by STIM1 Binding. PLoS ONE 2015, 10, e0128622. [Google Scholar] [CrossRef]
- Kim, K.M.; Wijerathne, T.; Hur, J.H.; Kang, U.J.; Kim, I.H.; Kweon, Y.C.; Lee, A.R.; Jeong, S.J.; Lee, S.K.; Lee, Y.Y.; et al. Distinct gating mechanism of SOC channel involving STIM-Orai coupling and an intramolecular interaction of Orai in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 2018, 115, E4623–E4632. [Google Scholar] [CrossRef] [Green Version]
- Ji, W.; Xu, P.; Li, Z.; Lu, J.; Liu, L.; Zhan, Y.; Chen, Y.; Hille, B.; Xu, T.; Chen, L. Functional stoichiometry of the unitary calcium-release-activated calcium channel. Proc. Natl. Acad. Sci. USA 2008, 105, 13668–13673. [Google Scholar] [CrossRef] [Green Version]
- Mignen, O.; Thompson, J.L.; Shuttleworth, T.J. Orai1 subunit stoichiometry of the mammalian CRAC channel pore. J. Physiol. 2008, 586, 419–425. [Google Scholar] [CrossRef]
- Penna, A.; Demuro, A.; Yeromin, A.V.; Zhang, S.L.; Safrina, O.; Parker, I.; Cahalan, M.D. The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers. Nature 2008, 456, 116–120. [Google Scholar] [CrossRef]
- Shuttleworth, T.J. Orai3--the ‘exceptional’ Orai? J. Physiol. 2012, 590, 241–257. [Google Scholar] [CrossRef]
- Fahrner, M.; Muik, M.; Derler, I.; Schindl, R.; Fritsch, R.; Frischauf, I.; Romanin, C. Mechanistic view on domains mediating STIM1-Orai coupling. Immunol. Rev. 2009, 231, 99–112. [Google Scholar] [CrossRef] [PubMed]
- Takahashi, Y.; Murakami, M.; Watanabe, H.; Hasegawa, H.; Ohba, T.; Munehisa, Y.; Nobori, K.; Ono, K.; Iijima, T.; Ito, H. Essential role of the N-terminus of murine Orai1 in store-operated Ca2+ entry. Biochem. Biophys. Res. Commun. 2007, 356, 45–52. [Google Scholar] [CrossRef] [PubMed]
- Lee, K.P.; Yuan, J.P.; Zeng, W.; So, I.; Worley, P.F.; Muallem, S. Molecular determinants of fast Ca2+-dependent inactivation and gating of the Orai channels. Proc. Natl. Acad. Sci. USA 2009, 106, 14687–14692. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Frischauf, I.; Schindl, R.; Bergsmann, J.; Derler, I.; Fahrner, M.; Muik, M.; Fritsch, R.; Lackner, B.; Groschner, K.; Romanin, C. Cooperativeness of Orai cytosolic domains tunes subtype-specific gating. J. Biol. Chem. 2011, 286, 8577–8584. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Putney, J.W. Pharmacology of store-operated calcium channels. Mol. Interv. 2010, 10, 209–218. [Google Scholar] [CrossRef] [PubMed]
- Derler, I.; Fritsch, R.; Schindl, R.; Romanin, C. CRAC inhibitors: Identification and potential. Expert Opin. Drug Discov. 2008, 3, 787–800. [Google Scholar] [CrossRef]
- Peinelt, C.; Lis, A.; Beck, A.; Fleig, A.; Penner, R. 2-Aminoethoxydiphenyl borate directly facilitates and indirectly inhibits STIM1-dependent gating of CRAC channels. J. Physiol. 2008, 586, 3061–3073. [Google Scholar] [CrossRef]
- Zhang, X.; Xin, P.; Yoast, R.E.; Emrich, S.M.; Johnson, M.T.; Pathak, T.; Benson, J.C.; Azimi, I.; Gill, D.L.; Monteith, G.R.; et al. Distinct pharmacological profiles of ORAI1, ORAI2, and ORAI3 channels. Cell Calcium 2020, 91, 102281. [Google Scholar] [CrossRef]
- Vaeth, M.; Yang, J.; Yamashita, M.; Zee, I.; Eckstein, M.; Knosp, C.; Kaufmann, U.; Karoly Jani, P.; Lacruz, R.S.; Flockerzi, V.; et al. ORAI2 modulates store-operated calcium entry and T cell-mediated immunity. Nat. Commun. 2017, 8, 14714. [Google Scholar] [CrossRef] [Green Version]
- Bogeski, I.; Kummerow, C.; Al-Ansary, D.; Schwarz, E.C.; Koehler, R.; Kozai, D.; Takahashi, N.; Peinelt, C.; Griesemer, D.; Bozem, M.; et al. Differential redox regulation of ORAI ion channels: A mechanism to tune cellular calcium signaling. Sci. Signal. 2010, 3, ra24. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Alansary, D.; Schmidt, B.; Dorr, K.; Bogeski, I.; Rieger, H.; Kless, A.; Niemeyer, B.A. Thiol dependent intramolecular locking of Orai1 channels. Sci. Rep. 2016, 6, 33347. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ishii, T.; Sato, K.; Kakumoto, T.; Miura, S.; Touhara, K.; Takeuchi, S.; Nakata, T. Light generation of intracellular Ca(2+) signals by a genetically encoded protein BACCS. Nat. Commun. 2015, 6, 8021. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- He, L.; Zhang, Y.; Ma, G.; Tan, P.; Li, Z.; Zang, S.; Wu, X.; Jing, J.; Fang, S.; Zhou, L.; et al. Near-infrared photoactivatable control of Ca(2+) signaling and optogenetic immunomodulation. eLife 2015, 4. [Google Scholar] [CrossRef] [PubMed]
- Ma, G.; Wen, S.; Huang, Y.; Zhou, Y. The STIM-Orai Pathway: Light-Operated Ca(2+) Entry Through Engineered CRAC Channels. Adv. Exp. Med. Biol. 2017, 993, 117–138. [Google Scholar]
- Parekh, A.B. Store-operated channels: Mechanisms and function. J. Physiol. 2008, 586, 3033. [Google Scholar] [CrossRef] [PubMed]
- Kar, P.; Parekh, A.B. Distinct spatial Ca2+ signatures selectively activate different NFAT transcription factor isoforms. Mol. Cell 2015, 58, 232–243. [Google Scholar] [CrossRef] [Green Version]
- Palty, R.; Raveh, A.; Kaminsky, I.; Meller, R.; Reuveny, E. SARAF inactivates the store operated calcium entry machinery to prevent excess calcium refilling. Cell 2012, 149, 425–438. [Google Scholar] [CrossRef] [Green Version]
- Jing, J.; He, L.; Sun, A.; Quintana, A.; Ding, Y.; Ma, G.; Tan, P.; Liang, X.; Zheng, X.; Chen, L.; et al. Proteomic mapping of ER-PM junctions identifies STIMATE as a regulator of Ca influx. Nat. Cell. Biol. 2015. [Google Scholar] [CrossRef] [Green Version]
- Bohorquez-Hernandez, A.; Gratton, E.; Pacheco, J.; Asanov, A.; Vaca, L. Cholesterol modulates the cellular localization of Orai1 channels and its disposition among membrane domains. Biochim. Biophys. Acta 2017, 1862, 1481–1490. [Google Scholar] [CrossRef]
- Derler, I.; Jardin, I.; Stathopulos, P.B.; Muik, M.; Fahrner, M.; Zayats, V.; Pandey, S.K.; Poteser, M.; Lackner, B.; Absolonova, M.; et al. Cholesterol modulates Orai1 channel function. Sci. Signal. 2016, 9, ra10. [Google Scholar] [CrossRef] [Green Version]
- Pacheco, J.; Dominguez, L.; Bohorquez-Hernandez, A.; Asanov, A.; Vaca, L. A cholesterol-binding domain in STIM1 modulates STIM1-Orai1 physical and functional interactions. Sci. Rep. 2016, 6, 29634. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Parekh, A.B. Store-operated CRAC channels: Function in health and disease. Nat. Rev. Drug Discov. 2010, 9, 399–410. [Google Scholar] [CrossRef] [PubMed]
- Jairaman, A.; Prakriya, M. Molecular pharmacology of store-operated CRAC channels. Channels 2013, 7, 402–414. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Inactive | Mutations in | Inactive | Mutations in | ||||||||||
N-Term | TM1 | TM2 | TM3 | TM4 | N-Term | TM1 | TM2 | TM3 | TM4 | ||||
CETR LoF | MTR GoF | K85E | L130S | MTR LoF | MTR GoF | H134W | V181K | ||||||
H134A | A235C | ||||||||||||
F136S | S239C | ||||||||||||
V181K | P245L | ||||||||||||
V181A | L138A | V181K | |||||||||||
L185A | F250A | V181F | A235C | ||||||||||
S239C | H134A | ||||||||||||
P245L | A235W | ||||||||||||
H134A | S239W | ||||||||||||
I148S | CETR | H134W | 265ANSGA265 | ||||||||||
I148S | V181K | A235W | |||||||||||
P245L | 265ANSGA265 | ||||||||||||
H134A | |||||||||||||
E149K | Active | Mutations in | |||||||||||
E149K | V181K | N-Term | TM1 | TM2 | TM3 | TM4 | |||||||
P245L | MTR LoF/LoFweak | MTR GoF | V102A | H134W | |||||||||
H134A | L174D | I148S | |||||||||||
A235C | E149K | ||||||||||||
S239C | L174D | ||||||||||||
P245L | S179F | ||||||||||||
L174D | F250A | H134A | L188S | ||||||||||
L185A | V191N | ||||||||||||
H134A | S179F | L194S | |||||||||||
F136S | M243S | ||||||||||||
A235C | H134A | ||||||||||||
S239C | T142C | ||||||||||||
P245L | CETR LoF | K85E | V102A | ||||||||||
CETR | K85E | 265ANSGA265 | H134A | 262AAA264 | |||||||||
262GGG264 | |||||||||||||
P245L | |||||||||||||
262AAA264 | |||||||||||||
P245L | |||||||||||||
262GGG264 | |||||||||||||
P245L | |||||||||||||
L261D |
Orai1 xx | |||||
---|---|---|---|---|---|
xx = | MTR LoF (e.g., H134W, S239W) | MTR LoFweak (e.g., L188S, …) | K85E LoF | CETR LoF (e.g., E149K, L174D) | Hinge LoF (e.g., 3xG, 3xA) |
Activation via STIM1 | inactive | ||||
Activation via OASF L251S | Slight activity | n.d. | inactive | ||
Coupling to OASF L251S | yes | reduced | |||
Activity in the presence of an MTR GoF | inactive | active | inactive | active | |
TM1 cysteine crosslinking | Corresponds to control conditions | n.d. | Corresponds to control conditions | n.d. | |
Hydration profile | Reduced number of water molecules | n.d. | Reduced number of water molecules | n.d. | |
Activity in the presence of a MTR GoF and SS | active | n.d. | inactive | n.d. | |
Activity within a dimer (Orai1 LoF–Orai1 GoF) | active | n.d. | inactive | n.d. | |
↓ | ↓ | ↓ | ↓ | ↓ | |
Control of | pore geometry (for activation by both STIM1 and GoF) | pore geometry (required for activation by STIM1 but not a GoF) | pore geometry (for activation by both STIM1 and GoF), partly STIM1 coupling | pore geometry (for activation by both STIM1 and GoF), STIM1 coupling | pore geometry (required for activation by STIM1 but not a GoF), STIM1 coupling |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Tiffner, A.; Maltan, L.; Weiß, S.; Derler, I. The Orai Pore Opening Mechanism. Int. J. Mol. Sci. 2021, 22, 533. https://doi.org/10.3390/ijms22020533
Tiffner A, Maltan L, Weiß S, Derler I. The Orai Pore Opening Mechanism. International Journal of Molecular Sciences. 2021; 22(2):533. https://doi.org/10.3390/ijms22020533
Chicago/Turabian StyleTiffner, Adéla, Lena Maltan, Sarah Weiß, and Isabella Derler. 2021. "The Orai Pore Opening Mechanism" International Journal of Molecular Sciences 22, no. 2: 533. https://doi.org/10.3390/ijms22020533