SOAR and the polybasic STIM1 domains gate and regulate Orai channels

Joseph P. Yuan, Weizhong Zeng, Michael R. Dorwart, Young Jin Choi, Paul F. Worley, Shmuel Muallem

Research output: Contribution to journalArticleResearchpeer-review

436 Citations (Scopus)

Abstract

Influx of Ca2+ through store-operated Ca2+ channels (SOCs) is a central component of receptor-evoked Ca2+ signals. Orai channels are SOCs that are gated by STIM1, a Ca2+ sensor located in the ER but how it gates and regulates the Orai channels is unknown. Here, we report the molecular basis for gating of Orais by STIM1. All Orai channels are fully activated by the conserved STIM1 amino acid fragment 344-442, which we termed SOAR (the STIM1 Orai activating region). SOAR acts in combination with STIM1 (450-485) to regulate the strength of interaction with Orai1. Activation of Orai1 by SOAR recapitulates all the kinetic properties of Orai1 activation by STIM1. However, mutations of STIM1 within SOAR prevent activation of Orai1 but not co-clustering of STIM1 and Orai1 in response to Ca2+ store depletion, indicating that STIM1-Orai1 co-clustering is not sufficient for Orai1 activation. An intact carboxy terminus α-helicial region of Orai is required for activation by SOAR. Deleting most of the Orai1 amino terminus impaired Orai1 activation by STIM1, but Orai1Δ1-73 interacted with and was fully activated by SOAR. Accordingly, the characteristic inward rectification of Orai is mediated by an interaction between the polybasic STIM1 (672-685) and a Pro-rich region in the N terminus of Orai1. Hence, the essential properties of Orai1 function can be rationalized by interactions with discrete regions of STIM1.

Original languageEnglish
Pages (from-to)337-343
Number of pages7
JournalNature Cell Biology
Volume11
Issue number3
DOIs
StatePublished - 2 Feb 2009

Fingerprint

Cluster Analysis
Amino Acids
Mutation

Cite this

Yuan, J. P., Zeng, W., Dorwart, M. R., Choi, Y. J., Worley, P. F., & Muallem, S. (2009). SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nature Cell Biology, 11(3), 337-343. https://doi.org/10.1038/ncb1842
Yuan, Joseph P. ; Zeng, Weizhong ; Dorwart, Michael R. ; Choi, Young Jin ; Worley, Paul F. ; Muallem, Shmuel. / SOAR and the polybasic STIM1 domains gate and regulate Orai channels. In: Nature Cell Biology. 2009 ; Vol. 11, No. 3. pp. 337-343.
@article{d9f7caf9d84a4c4a802337ef95d215d2,
title = "SOAR and the polybasic STIM1 domains gate and regulate Orai channels",
abstract = "Influx of Ca2+ through store-operated Ca2+ channels (SOCs) is a central component of receptor-evoked Ca2+ signals. Orai channels are SOCs that are gated by STIM1, a Ca2+ sensor located in the ER but how it gates and regulates the Orai channels is unknown. Here, we report the molecular basis for gating of Orais by STIM1. All Orai channels are fully activated by the conserved STIM1 amino acid fragment 344-442, which we termed SOAR (the STIM1 Orai activating region). SOAR acts in combination with STIM1 (450-485) to regulate the strength of interaction with Orai1. Activation of Orai1 by SOAR recapitulates all the kinetic properties of Orai1 activation by STIM1. However, mutations of STIM1 within SOAR prevent activation of Orai1 but not co-clustering of STIM1 and Orai1 in response to Ca2+ store depletion, indicating that STIM1-Orai1 co-clustering is not sufficient for Orai1 activation. An intact carboxy terminus α-helicial region of Orai is required for activation by SOAR. Deleting most of the Orai1 amino terminus impaired Orai1 activation by STIM1, but Orai1Δ1-73 interacted with and was fully activated by SOAR. Accordingly, the characteristic inward rectification of Orai is mediated by an interaction between the polybasic STIM1 (672-685) and a Pro-rich region in the N terminus of Orai1. Hence, the essential properties of Orai1 function can be rationalized by interactions with discrete regions of STIM1.",
author = "Yuan, {Joseph P.} and Weizhong Zeng and Dorwart, {Michael R.} and Choi, {Young Jin} and Worley, {Paul F.} and Shmuel Muallem",
year = "2009",
month = "2",
day = "2",
doi = "10.1038/ncb1842",
language = "English",
volume = "11",
pages = "337--343",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "3",

}

Yuan, JP, Zeng, W, Dorwart, MR, Choi, YJ, Worley, PF & Muallem, S 2009, 'SOAR and the polybasic STIM1 domains gate and regulate Orai channels', Nature Cell Biology, vol. 11, no. 3, pp. 337-343. https://doi.org/10.1038/ncb1842

SOAR and the polybasic STIM1 domains gate and regulate Orai channels. / Yuan, Joseph P.; Zeng, Weizhong; Dorwart, Michael R.; Choi, Young Jin; Worley, Paul F.; Muallem, Shmuel.

In: Nature Cell Biology, Vol. 11, No. 3, 02.02.2009, p. 337-343.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - SOAR and the polybasic STIM1 domains gate and regulate Orai channels

AU - Yuan, Joseph P.

AU - Zeng, Weizhong

AU - Dorwart, Michael R.

AU - Choi, Young Jin

AU - Worley, Paul F.

AU - Muallem, Shmuel

PY - 2009/2/2

Y1 - 2009/2/2

N2 - Influx of Ca2+ through store-operated Ca2+ channels (SOCs) is a central component of receptor-evoked Ca2+ signals. Orai channels are SOCs that are gated by STIM1, a Ca2+ sensor located in the ER but how it gates and regulates the Orai channels is unknown. Here, we report the molecular basis for gating of Orais by STIM1. All Orai channels are fully activated by the conserved STIM1 amino acid fragment 344-442, which we termed SOAR (the STIM1 Orai activating region). SOAR acts in combination with STIM1 (450-485) to regulate the strength of interaction with Orai1. Activation of Orai1 by SOAR recapitulates all the kinetic properties of Orai1 activation by STIM1. However, mutations of STIM1 within SOAR prevent activation of Orai1 but not co-clustering of STIM1 and Orai1 in response to Ca2+ store depletion, indicating that STIM1-Orai1 co-clustering is not sufficient for Orai1 activation. An intact carboxy terminus α-helicial region of Orai is required for activation by SOAR. Deleting most of the Orai1 amino terminus impaired Orai1 activation by STIM1, but Orai1Δ1-73 interacted with and was fully activated by SOAR. Accordingly, the characteristic inward rectification of Orai is mediated by an interaction between the polybasic STIM1 (672-685) and a Pro-rich region in the N terminus of Orai1. Hence, the essential properties of Orai1 function can be rationalized by interactions with discrete regions of STIM1.

AB - Influx of Ca2+ through store-operated Ca2+ channels (SOCs) is a central component of receptor-evoked Ca2+ signals. Orai channels are SOCs that are gated by STIM1, a Ca2+ sensor located in the ER but how it gates and regulates the Orai channels is unknown. Here, we report the molecular basis for gating of Orais by STIM1. All Orai channels are fully activated by the conserved STIM1 amino acid fragment 344-442, which we termed SOAR (the STIM1 Orai activating region). SOAR acts in combination with STIM1 (450-485) to regulate the strength of interaction with Orai1. Activation of Orai1 by SOAR recapitulates all the kinetic properties of Orai1 activation by STIM1. However, mutations of STIM1 within SOAR prevent activation of Orai1 but not co-clustering of STIM1 and Orai1 in response to Ca2+ store depletion, indicating that STIM1-Orai1 co-clustering is not sufficient for Orai1 activation. An intact carboxy terminus α-helicial region of Orai is required for activation by SOAR. Deleting most of the Orai1 amino terminus impaired Orai1 activation by STIM1, but Orai1Δ1-73 interacted with and was fully activated by SOAR. Accordingly, the characteristic inward rectification of Orai is mediated by an interaction between the polybasic STIM1 (672-685) and a Pro-rich region in the N terminus of Orai1. Hence, the essential properties of Orai1 function can be rationalized by interactions with discrete regions of STIM1.

UR - http://www.scopus.com/inward/record.url?scp=61849107063&partnerID=8YFLogxK

U2 - 10.1038/ncb1842

DO - 10.1038/ncb1842

M3 - Article

VL - 11

SP - 337

EP - 343

JO - Nature Cell Biology

JF - Nature Cell Biology

SN - 1465-7392

IS - 3

ER -