Related Experiment Video

Updated: Mar 26, 2026

Targeting Cysteine Thiols for in Vitro Site-specific Glycosylation of Recombinant Proteins

Targeting Cysteine Thiols for in Vitro Site-specific Glycosylation of Recombinant Proteins

Published on: October 4, 2017

Molecular mechanisms of STIM/Orai communication

Isabella Derler¹, Isaac Jardin², Christoph Romanin³

¹Institute of Biophysics, Johannes Kepler University of Linz, Linz, Austria; and.

American Journal of Physiology. Cell Physiology

|January 31, 2016

Abstract:

Ca(2+)entry into the cell via store-operated Ca(2+)release-activated Ca(2+)(CRAC) channels triggers diverse signaling cascades that affect cellular processes like cell growth, gene regulation, secretion, and cell death. These store-operated Ca(2+)channels open after depletion of intracellular Ca(2+)stores, and their main features are fully reconstituted by the two molecular key players: the stromal interaction molecule (STIM) and Orai. STIM represents an endoplasmic reticulum-located Ca(2+)sensor, while Orai forms a highly Ca(2+)-selective ion channel in the plasma membrane. 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.

Insights

Stromal interaction molecule (STIM) and Orai proteins form store-operated calcium release-activated calcium (CRAC) channels. This review details the STIM1-Orai1 interaction mechanism, crucial for cellular calcium signaling.

Area of Science:

Cellular Biology
Molecular Biology
Biochemistry

Background:

Store-operated calcium (Ca2+) entry via CRAC channels regulates vital cellular processes.
STIM and Orai proteins are the key molecular components reconstituting CRAC channel function.
STIM acts as an endoplasmic reticulum Ca2+ sensor, while Orai forms the plasma membrane Ca2+ channel.

Purpose of the Study:

To review experimental advances in understanding the STIM1-Orai1 interaction in CRAC channel signaling.
To elucidate the mechanistic steps involved in CRAC channel activation.
To provide a molecular portrait of STIM-Orai choreography.

Main Methods:

Functional studies of STIM and Orai proteins.
Mutagenesis studies to identify key residues.
Structural insights into STIM-Orai complex formation.
Review of experimental advances in CRAC channel research.

Main Results:

STIM1 activation upon ER Ca2+ store depletion.
STIM1 coupling to Orai1.
Structural rearrangements in Orai1 gating upon STIM1 interaction.
Ca2+ permeation through the opened Orai1 channel.

Conclusions:

The STIM1-Orai1 interaction is a precisely orchestrated process essential for CRAC channel function.
Understanding this choreography reveals key mechanistic steps in cellular calcium signaling.
This review consolidates current knowledge on STIM-Orai interplay in CRAC channel activation.

Read full analysis

Keywords:

CRAC channel Orai Orai gating STIM-Orai interaction STIM1

More Related Videos

Mechanical Stimulation-induced Calcium Wave Propagation in Cell Monolayers: The Example of Bovine Corneal Endothelial Cells

Mechanical Stimulation-induced Calcium Wave Propagation in Cell Monolayers: The Example of Bovine Corneal Endothelial Cells

Published on: July 16, 2013

Isolation of Human Myoblasts, Assessment of Myogenic Differentiation, and Store-operated Calcium Entry Measurement

Isolation of Human Myoblasts, Assessment of Myogenic Differentiation, and Store-operated Calcium Entry Measurement

Published on: July 26, 2017

Related Concept Videos

Amplifying Signals via Second Messengers

Amplifying Signals via Second Messengers

Many receptor binding ligands are hydrophilic; they do not cross the cell membrane but bind to cell-surface receptors. Thus, their message must be relayed by second messengers present in the cell cytoplasm. There are several second messenger pathways, each with its own way of relaying information. For example, the G protein-coupled receptors can activate both phosphoinositol and cyclic AMP (cAMP) second messenger pathways. The phosphoinositol pathway is active when the receptor induces...

Types of Signaling Molecules

Types of Signaling Molecules

In multicellular organisms, many molecules transmit signals between cells to pass information. These signals vary in complexity and include small peptides, nucleotides, steroids, fatty acid derivatives, and dissolved gases such as nitric oxide. Some signaling molecules diffuse through the plasma membrane to act locally between neighboring cells or travel long distances. Others remain attached to the cell surface, transmitting information to other cells only when they make contact. In some...

Types of Signaling Molecules

Types of Signaling Molecules

Calmodulin-dependent Signaling

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...

What are Second Messengers?

What are Second Messengers?

Because many receptor binding ligands are hydrophilic, they do not cross the cell membrane and thus their message must be relayed to a second messenger on the inside. There are several second messenger pathways, each with their own way of relaying information. G-protein coupled receptors can activate both phosphoinositol and cyclic AMP (cAMP) second messenger pathways. The phosphoinositol path is active when the receptor induces phospholipase C to hydrolyze the phospholipid,...

What are Second Messengers?

What are Second Messengers?

Articles linked to this work by shared authors, journal, and citation graph.

The many faces of Orai1 dysfunction: Molecular mechanisms and clinical manifestations.

The Journal of general physiology·2026

Evolutionarily conserved hydrophobicity and sterics in TM3/TM4 balance Orai1 pore opening.

Protein science : a publication of the Protein Society·2026

Canonical and noncanonical heterotrimeric G-protein signaling in uveal melanoma: Established mechanisms and emerging spindle-orientation hypotheses.

Biochemical pharmacology·2026

STIM1 GoF Mutants: Genotype-Phenotype Relationships Across the Stormorken/TAM/YPS Spectrum.

Cells·2026

Mechanistic insights into Orai dynamics during pore opening.

Channels (Austin, Tex.)·2026

Distances and charges along the Orai1 nexus-TM3 interface control STIM1 binding and pore opening.

Cell reports·2026

See all related articles