Splicing reverses protein’s function

Alternative splicing transforms a protein that stimulates calcium uptake into one that inhibits it, Rana et al. discover.

The proteins STIM1 and STIM2 sense when the endoplasmic reticulum is running low on calcium. They then prod Orai channels in the plasma membrane to open and allow more calcium into the cell through a process called store-operated calcium entry.

Rana et al. identified a second isoform of STIM2 that arises by alternative splicing. This version, STIM2β, carried an eight-amino-acid insert that was absent from the previously identified isoform, STIM2α. The exon encoding this segment was well conserved in mammals, and its splicing was regulated during tissue development, suggesting that it has an important function.

Surprisingly, Rana et al. found that STIM2β blocks calcium influx through the Orai1 channel. Unlike STIM1 and STIM2α, STIM2β can’t bind to Orai1. It reaches the channel by hitching a ride with STIM1 or STIM2α.

How it blocks the channel once it gets there remains unclear. The inhibition appears to involve a specific interaction between STIM2β and Orai1, because mutations in the eight-amino-acid insert of STIM2β strongly reduce the inhibition. The authors think that having the option of producing STIM2β might enable cells to tune the strength or dynamics of their calcium signals.