Activation of STIM1-Orai1 involves an intramolecular switching mechanism

Marek K. Korzeniowski, Isabel Martín Manjarrés, P. Várnai, Tamas Balla

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

Stromal interaction molecule 1 (STIM1) stimulates calcium ion (Ca 2+) entry through plasma membrane Orai1 channels in response to decreased Ca2+ concentrations in the endoplasmic reticulum lumen. We identified an acidic motif within the STIM1 coiled-coil region that keeps its Ca2+ activation domain [Ca2+ release-activated Ca 2+ (CRAC) activation domain/STIM1-Orai activating region (CAD/SOAR)] - a cytoplasmic region required for its activation of Orai1 - inactive. The sequence of the STIM1 acidic motif shows substantial similarity to that of the carboxyl-terminal coiled-coil segment of Orai1, which is the postulated site of interaction with STIM1. Mutations within this acidic region rendered STIM1 constitutively active, whereas mutations within a short basic segment of CAD/SOAR prevented Orai1 activation. We propose that the CAD/SOAR domain is released from an intramolecular clamp during STIM1 activation, allowing the basic segment to activate Orai1 channels. This evolutionarily conserved mechanism of STIM1 activation resembles the regulation of protein kinases by intramolecular silencing through pseudosubstrate binding.

Original languageEnglish
Article numberra82
JournalScience Signaling
Volume3
Issue number148
DOIs
Publication statusPublished - Nov 16 2010

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Chemical activation
Molecules
Mutation
Stromal Interaction Molecule 1
Clamping devices
Cell membranes
Ion Channels
Endoplasmic Reticulum
Protein Kinases
Cell Membrane
Ions
Calcium

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Activation of STIM1-Orai1 involves an intramolecular switching mechanism. / Korzeniowski, Marek K.; Manjarrés, Isabel Martín; Várnai, P.; Balla, Tamas.

In: Science Signaling, Vol. 3, No. 148, ra82, 16.11.2010.

Research output: Contribution to journalArticle

Korzeniowski, Marek K. ; Manjarrés, Isabel Martín ; Várnai, P. ; Balla, Tamas. / Activation of STIM1-Orai1 involves an intramolecular switching mechanism. In: Science Signaling. 2010 ; Vol. 3, No. 148.
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