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Molecular mechanisms of STIM/Orai communication.

Derler I, Jardin I, Romanin C - Am. J. Physiol., Cell Physiol. (2016)

Bottom Line: Functional as well as mutagenesis studies together with structural insights about STIM and Orai proteins provide a molecular picture of the interplay of these two key players in the CRAC signaling cascade.This review focuses on the main experimental advances in the understanding of the STIM1-Orai choreography, thereby establishing a portrait of key mechanistic steps in the CRAC channel signaling cascade.The focus is on the activation of the STIM proteins, the subsequent coupling of STIM1 to Orai1, and the consequent structural rearrangements that gate the Orai channels into the open state to allow Ca(2+)permeation into the cell.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biophysics, Johannes Kepler University of Linz, Linz, Austria; and.

No MeSH data available.


Orai1. A: scheme that represents full-length human Orai1 with its overall structure and residues required for Orai1 function. B: cartoon depicting the hexameric assembly of Orai subunits based on the X-ray crystal structure of Drosophila (d)Orai. Transmembrane domain (TM)1 forms the inner ring surrounding the ion-conducting pore, while the other TM domains of the 6 subunits are arranged as concentric rings around the pore. C: cartoon depicts the human Orai1 pore by 2 TM1 strands together with the cytosolic, helical extensions including the conserved extended transmembrane Orai1 NH2-terminal (ETON) region at the NH2-terminal side of TM1 as well as the Ca2+ accumulating region (CAR) region at the COOH-terminal side of TM1, as part of the loop1 region connecting TM1 and TM2. Essential regions in the pore such as the selectivity filter, the hydrophobic core, as well as residues within the ETON region are highlighted. D: cartoon representation of a single Orai1 subunit with the 4 TM regions and the NH2- as well as COOH-terminal elongated helices, depicted in distinct colors used throughout A–D. Moreover, all 4 TM domains, the COOH terminus, and the NH2 terminus are shown separately with those residues relevant to Orai1 function highlighted [amino acid (aa) numbering refers to human Orai1].
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Figure 2: Orai1. A: scheme that represents full-length human Orai1 with its overall structure and residues required for Orai1 function. B: cartoon depicting the hexameric assembly of Orai subunits based on the X-ray crystal structure of Drosophila (d)Orai. Transmembrane domain (TM)1 forms the inner ring surrounding the ion-conducting pore, while the other TM domains of the 6 subunits are arranged as concentric rings around the pore. C: cartoon depicts the human Orai1 pore by 2 TM1 strands together with the cytosolic, helical extensions including the conserved extended transmembrane Orai1 NH2-terminal (ETON) region at the NH2-terminal side of TM1 as well as the Ca2+ accumulating region (CAR) region at the COOH-terminal side of TM1, as part of the loop1 region connecting TM1 and TM2. Essential regions in the pore such as the selectivity filter, the hydrophobic core, as well as residues within the ETON region are highlighted. D: cartoon representation of a single Orai1 subunit with the 4 TM regions and the NH2- as well as COOH-terminal elongated helices, depicted in distinct colors used throughout A–D. Moreover, all 4 TM domains, the COOH terminus, and the NH2 terminus are shown separately with those residues relevant to Orai1 function highlighted [amino acid (aa) numbering refers to human Orai1].

Mentions: Orai proteins (Fig. 2) represent Ca2+-selective ion channels in the PM including three highly conserved homologs, termed Orai1-3 (15, 46, 170, 170). Each Orai monomer contains four TM segments linked via one intracellular and two extracellular loops and cytosolic NH2 and COOH termini (68, 105, 124) (Fig. 2A). The TM regions share ∼81–87% pairwise sequence identity, whereas TM1 is fully conserved among Orai proteins. The cytosolic strands, extra- and intracellular loops are less conserved, except for segments involved in direct binding of STIM1 (58). Major structural differences are found in extracellular loop3, which is much longer in Orai3, as well as in the cytosolic NH2 and COOH termini, which share 34% and 46% sequence homology, respectively (148). Both cytosolic strands of Orai are required for functional coupling to STIM1 (35, 80, 100, 111, 115, 121, 189). STIM1-mediated Orai currents display strongly inward-rectifying Ca2+ currents and a low single-channel conductance similar to what has been reported for endogenous CRAC channels (86).


Molecular mechanisms of STIM/Orai communication.

Derler I, Jardin I, Romanin C - Am. J. Physiol., Cell Physiol. (2016)

Orai1. A: scheme that represents full-length human Orai1 with its overall structure and residues required for Orai1 function. B: cartoon depicting the hexameric assembly of Orai subunits based on the X-ray crystal structure of Drosophila (d)Orai. Transmembrane domain (TM)1 forms the inner ring surrounding the ion-conducting pore, while the other TM domains of the 6 subunits are arranged as concentric rings around the pore. C: cartoon depicts the human Orai1 pore by 2 TM1 strands together with the cytosolic, helical extensions including the conserved extended transmembrane Orai1 NH2-terminal (ETON) region at the NH2-terminal side of TM1 as well as the Ca2+ accumulating region (CAR) region at the COOH-terminal side of TM1, as part of the loop1 region connecting TM1 and TM2. Essential regions in the pore such as the selectivity filter, the hydrophobic core, as well as residues within the ETON region are highlighted. D: cartoon representation of a single Orai1 subunit with the 4 TM regions and the NH2- as well as COOH-terminal elongated helices, depicted in distinct colors used throughout A–D. Moreover, all 4 TM domains, the COOH terminus, and the NH2 terminus are shown separately with those residues relevant to Orai1 function highlighted [amino acid (aa) numbering refers to human Orai1].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 2: Orai1. A: scheme that represents full-length human Orai1 with its overall structure and residues required for Orai1 function. B: cartoon depicting the hexameric assembly of Orai subunits based on the X-ray crystal structure of Drosophila (d)Orai. Transmembrane domain (TM)1 forms the inner ring surrounding the ion-conducting pore, while the other TM domains of the 6 subunits are arranged as concentric rings around the pore. C: cartoon depicts the human Orai1 pore by 2 TM1 strands together with the cytosolic, helical extensions including the conserved extended transmembrane Orai1 NH2-terminal (ETON) region at the NH2-terminal side of TM1 as well as the Ca2+ accumulating region (CAR) region at the COOH-terminal side of TM1, as part of the loop1 region connecting TM1 and TM2. Essential regions in the pore such as the selectivity filter, the hydrophobic core, as well as residues within the ETON region are highlighted. D: cartoon representation of a single Orai1 subunit with the 4 TM regions and the NH2- as well as COOH-terminal elongated helices, depicted in distinct colors used throughout A–D. Moreover, all 4 TM domains, the COOH terminus, and the NH2 terminus are shown separately with those residues relevant to Orai1 function highlighted [amino acid (aa) numbering refers to human Orai1].
Mentions: Orai proteins (Fig. 2) represent Ca2+-selective ion channels in the PM including three highly conserved homologs, termed Orai1-3 (15, 46, 170, 170). Each Orai monomer contains four TM segments linked via one intracellular and two extracellular loops and cytosolic NH2 and COOH termini (68, 105, 124) (Fig. 2A). The TM regions share ∼81–87% pairwise sequence identity, whereas TM1 is fully conserved among Orai proteins. The cytosolic strands, extra- and intracellular loops are less conserved, except for segments involved in direct binding of STIM1 (58). Major structural differences are found in extracellular loop3, which is much longer in Orai3, as well as in the cytosolic NH2 and COOH termini, which share 34% and 46% sequence homology, respectively (148). Both cytosolic strands of Orai are required for functional coupling to STIM1 (35, 80, 100, 111, 115, 121, 189). STIM1-mediated Orai currents display strongly inward-rectifying Ca2+ currents and a low single-channel conductance similar to what has been reported for endogenous CRAC channels (86).

Bottom Line: Functional as well as mutagenesis studies together with structural insights about STIM and Orai proteins provide a molecular picture of the interplay of these two key players in the CRAC signaling cascade.This review focuses on the main experimental advances in the understanding of the STIM1-Orai choreography, thereby establishing a portrait of key mechanistic steps in the CRAC channel signaling cascade.The focus is on the activation of the STIM proteins, the subsequent coupling of STIM1 to Orai1, and the consequent structural rearrangements that gate the Orai channels into the open state to allow Ca(2+)permeation into the cell.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biophysics, Johannes Kepler University of Linz, Linz, Austria; and.

No MeSH data available.