An open pore structure of the Orai channel, finally.

Store-operated Orai channels are a primary mechanism for mobilizing Ca signals in both non-excitable cells and excitable cells. The structure of the open channel, vital for understanding the mechanism of channel opening, is incompletely understood. We highlight a new study that unveils the structure of a constitutively active Orai mutant and takes us closer towards understanding the molecular basis of Orai channel activation.

MCU meets cardiolipin: Calcium and disease follow form.

Cardiolipin (CL) is a cone-shaped lipid found nearly exclusively in the inner mitochondrial membrane of animal cells. Disruption of CL synthesis leads to abnormalities in mitochondrial shape and function, but the underlying causes are incompletely understood. We highlight a new study that reveals that the activity of the mitochondrial calcium uniporter (MCU) is regulated by CL, advancing our understanding of the mechanisms of CL-linked human disease.

The basic residues in the Orai1 channel inner pore promote opening of the outer hydrophobic gate.

Store-operated Orai1 channels regulate a wide range of cellular functions from gene expression to cell proliferation. Previous studies have shown that gating of Orai1 channels is regulated by the outer pore residues V102 and F99, which together function as a hydrophobic gate to block ion conduction in resting channels. Opening of this gate occurs through a conformational change that moves F99 away from the permeation pathway, leading to pore hydration and ion conduction.

Molecular basis of allosteric Orai1 channel activation by STIM1.

Store-operated Ca entry through Orai1 channels is a primary mechanism for Ca entry in many cells and mediates numerous cellular effector functions ranging from gene transcription to exocytosis. Orai1 channels are amongst the most Ca -selective channels known and are activated by direct physical interactions with the endoplasmic reticulum Ca sensor stromal interaction molecule 1 (STIM1) in response to store depletion triggered by stimulation of a variety of cell surface G-protein coupled and tyrosine kinase receptors. Work in the last decade has revealed that the Orai1 gating process is highly cooperative and strongly allosteric, likely driven by a wave of interdependent conformational changes throughout the protein originating in the peripheral C-terminal ligand binding site and culminating in pore opening.

The exquisitely cooperative nature of Orai1 channel activation.

Yeung and Prakriya highlight new research showing that STIM1 must bind to all six Orai1 subunits to effectively activate the channel.