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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.


A and B: cartoons representing a hypothetical model for the coupling of STIM1 and Orai1. After store depletion, STIM1 proteins lose the Ca2+ bound to the luminal EF-hand and undergo a conformational change from the inactive, tight state (A) to the active, extended state (B). Thereby, the crossing angle of the TM helices alters and the inhibitory, intramolecular clamp between CC1α1 and CC3 is released. C: extension of STIM1 proteins leads to the interaction with Orai1, is accompanied by oligomerization of STIM1 proteins to larger aggregates than dimers, and involves the CC3 domains. Inset depicts intermolecular interactions between the STIM1 CC1α3-CC2 and Orai1 COOH terminus in the STIM1-Orai1 association pocket. PM, plasma membrane.
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Figure 3: A and B: cartoons representing a hypothetical model for the coupling of STIM1 and Orai1. After store depletion, STIM1 proteins lose the Ca2+ bound to the luminal EF-hand and undergo a conformational change from the inactive, tight state (A) to the active, extended state (B). Thereby, the crossing angle of the TM helices alters and the inhibitory, intramolecular clamp between CC1α1 and CC3 is released. C: extension of STIM1 proteins leads to the interaction with Orai1, is accompanied by oligomerization of STIM1 proteins to larger aggregates than dimers, and involves the CC3 domains. Inset depicts intermolecular interactions between the STIM1 CC1α3-CC2 and Orai1 COOH terminus in the STIM1-Orai1 association pocket. PM, plasma membrane.

Mentions: Loss of Ca2+ binding at the luminal EF-SAM domain triggers conformational changes in the NH2 terminus that are transmitted via the TM domain to the COOH terminus, finally culminating in the interaction with and activation of Orai channels (Fig. 3) (132). Based on an elegant study by Luik et al. (90) in which artificial luminal cross-linking of STIM1 was utilized, it is suggested that initial di- and/or oligomerization on the luminal side of STIM1 represents the first step in the activation cascade of STIM1.


Molecular mechanisms of STIM/Orai communication.

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

A and B: cartoons representing a hypothetical model for the coupling of STIM1 and Orai1. After store depletion, STIM1 proteins lose the Ca2+ bound to the luminal EF-hand and undergo a conformational change from the inactive, tight state (A) to the active, extended state (B). Thereby, the crossing angle of the TM helices alters and the inhibitory, intramolecular clamp between CC1α1 and CC3 is released. C: extension of STIM1 proteins leads to the interaction with Orai1, is accompanied by oligomerization of STIM1 proteins to larger aggregates than dimers, and involves the CC3 domains. Inset depicts intermolecular interactions between the STIM1 CC1α3-CC2 and Orai1 COOH terminus in the STIM1-Orai1 association pocket. PM, plasma membrane.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835918&req=5

Figure 3: A and B: cartoons representing a hypothetical model for the coupling of STIM1 and Orai1. After store depletion, STIM1 proteins lose the Ca2+ bound to the luminal EF-hand and undergo a conformational change from the inactive, tight state (A) to the active, extended state (B). Thereby, the crossing angle of the TM helices alters and the inhibitory, intramolecular clamp between CC1α1 and CC3 is released. C: extension of STIM1 proteins leads to the interaction with Orai1, is accompanied by oligomerization of STIM1 proteins to larger aggregates than dimers, and involves the CC3 domains. Inset depicts intermolecular interactions between the STIM1 CC1α3-CC2 and Orai1 COOH terminus in the STIM1-Orai1 association pocket. PM, plasma membrane.
Mentions: Loss of Ca2+ binding at the luminal EF-SAM domain triggers conformational changes in the NH2 terminus that are transmitted via the TM domain to the COOH terminus, finally culminating in the interaction with and activation of Orai channels (Fig. 3) (132). Based on an elegant study by Luik et al. (90) in which artificial luminal cross-linking of STIM1 was utilized, it is suggested that initial di- and/or oligomerization on the luminal side of STIM1 represents the first step in the activation cascade of STIM1.

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.