Tags

Type your tag names separated by a space and hit enter

Authentic CRAC channel activity requires STIM1 and the conserved portion of the Orai N terminus.
J Biol Chem. 2018 01 26; 293(4):1259-1270.JB

Abstract

Calcium (Ca2+) is an essential second messenger required for diverse signaling processes in immune cells. Ca2+ release-activated Ca2+ (CRAC) channels represent one main Ca2+ entry pathway into the cell. They are fully reconstituted via two proteins, the stromal interaction molecule 1 (STIM1), a Ca2+ sensor in the endoplasmic reticulum, and the Ca2+ ion channel Orai in the plasma membrane. After Ca2+ store depletion, STIM1 and Orai couple to each other, allowing Ca2+ influx. CRAC-/STIM1-mediated Orai channel currents display characteristic hallmarks such as high Ca2+ selectivity, an increase in current density when switching from a Ca2+-containing solution to a divalent-free Na+ one, and fast Ca2+-dependent inactivation. Here, we discovered several constitutively active Orai1 and Orai3 mutants, containing substitutions in the TM3 and/or TM4 regions, all of which displayed a loss of the typical CRAC channel hallmarks. Restoring authentic CRAC channel activity required both the presence of STIM1 and the conserved Orai N-terminal portion. Similarly, these structural requisites were found in store-operated Orai channels. Key molecular determinants within the Orai N terminus that together with STIM1 maintained the typical CRAC channel hallmarks were distinct from those that controlled store-dependent Orai activation. In conclusion, the conserved portion of the Orai N terminus is essential for STIM1, as it fine-tunes the open Orai channel gating, thereby establishing authentic CRAC channel activity.

Authors+Show Affiliations

From the Institute of Biophysics, Johannes Kepler University of Linz, Gruberstrasse 40, 4020 Linz, Austria Isabella.derler@jku.at.From the Institute of Biophysics, Johannes Kepler University of Linz, Gruberstrasse 40, 4020 Linz, Austria.From the Institute of Biophysics, Johannes Kepler University of Linz, Gruberstrasse 40, 4020 Linz, Austria.From the Institute of Biophysics, Johannes Kepler University of Linz, Gruberstrasse 40, 4020 Linz, Austria.From the Institute of Biophysics, Johannes Kepler University of Linz, Gruberstrasse 40, 4020 Linz, Austria.From the Institute of Biophysics, Johannes Kepler University of Linz, Gruberstrasse 40, 4020 Linz, Austria.From the Institute of Biophysics, Johannes Kepler University of Linz, Gruberstrasse 40, 4020 Linz, Austria.From the Institute of Biophysics, Johannes Kepler University of Linz, Gruberstrasse 40, 4020 Linz, Austria christoph.romanin@jku.at.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29237734

Citation

Derler, Isabella, et al. "Authentic CRAC Channel Activity Requires STIM1 and the Conserved Portion of the Orai N Terminus." The Journal of Biological Chemistry, vol. 293, no. 4, 2018, pp. 1259-1270.
Derler I, Butorac C, Krizova A, et al. Authentic CRAC channel activity requires STIM1 and the conserved portion of the Orai N terminus. J Biol Chem. 2018;293(4):1259-1270.
Derler, I., Butorac, C., Krizova, A., Stadlbauer, M., Muik, M., Fahrner, M., Frischauf, I., & Romanin, C. (2018). Authentic CRAC channel activity requires STIM1 and the conserved portion of the Orai N terminus. The Journal of Biological Chemistry, 293(4), 1259-1270. https://doi.org/10.1074/jbc.M117.812206
Derler I, et al. Authentic CRAC Channel Activity Requires STIM1 and the Conserved Portion of the Orai N Terminus. J Biol Chem. 2018 01 26;293(4):1259-1270. PubMed PMID: 29237734.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Authentic CRAC channel activity requires STIM1 and the conserved portion of the Orai N terminus. AU - Derler,Isabella, AU - Butorac,Carmen, AU - Krizova,Adéla, AU - Stadlbauer,Michael, AU - Muik,Martin, AU - Fahrner,Marc, AU - Frischauf,Irene, AU - Romanin,Christoph, Y1 - 2017/12/13/ PY - 2017/08/16/received PY - 2017/11/23/revised PY - 2017/12/15/pubmed PY - 2018/11/28/medline PY - 2017/12/15/entrez KW - calcium channel KW - calcium release-activated calcium channel protein 1 (ORAI1) KW - calcium-dependent inactivation KW - electrophysiology KW - signal transduction KW - sodium permeation KW - stromal interaction molecule 1 (STIM1) SP - 1259 EP - 1270 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 293 IS - 4 N2 - Calcium (Ca2+) is an essential second messenger required for diverse signaling processes in immune cells. Ca2+ release-activated Ca2+ (CRAC) channels represent one main Ca2+ entry pathway into the cell. They are fully reconstituted via two proteins, the stromal interaction molecule 1 (STIM1), a Ca2+ sensor in the endoplasmic reticulum, and the Ca2+ ion channel Orai in the plasma membrane. After Ca2+ store depletion, STIM1 and Orai couple to each other, allowing Ca2+ influx. CRAC-/STIM1-mediated Orai channel currents display characteristic hallmarks such as high Ca2+ selectivity, an increase in current density when switching from a Ca2+-containing solution to a divalent-free Na+ one, and fast Ca2+-dependent inactivation. Here, we discovered several constitutively active Orai1 and Orai3 mutants, containing substitutions in the TM3 and/or TM4 regions, all of which displayed a loss of the typical CRAC channel hallmarks. Restoring authentic CRAC channel activity required both the presence of STIM1 and the conserved Orai N-terminal portion. Similarly, these structural requisites were found in store-operated Orai channels. Key molecular determinants within the Orai N terminus that together with STIM1 maintained the typical CRAC channel hallmarks were distinct from those that controlled store-dependent Orai activation. In conclusion, the conserved portion of the Orai N terminus is essential for STIM1, as it fine-tunes the open Orai channel gating, thereby establishing authentic CRAC channel activity. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/29237734/Authentic_CRAC_channel_activity_requires_STIM1_and_the_conserved_portion_of_the_Orai_N_terminus_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=29237734 DB - PRIME DP - Unbound Medicine ER -