Splicing reverses protein’s function

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. identifi ed a second isoform of STIM2 that arises by alternative splicing. This version, STIM2 , carried an eight-amino-acid insert that was absent from the previously identifi ed isoform, STIM2 . 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 STIM2 blocks calcium infl ux through the Orai1 channel. Unlike STIM1 and STIM2 , STIM2 can’t bind to Orai1. It reaches the channel by hitching a ride with STIM1 or STIM2 . How it blocks the channel once it gets there remains unclear. The inhibition appears to involve a specifi c interaction between STIM2 and Orai1, because mutations in the eight-amino-acid insert of STIM2 strongly reduce the inhibition. The authors think that having the option of producing STIM2 might enable cells to tune the strength or dynamics of their calcium signals. Rana, A., et al. 2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201412060