Ca2+-calmodulin inhibits tail-anchored protein insertion into the mammalian endoplasmic reticulum membrane

► We analyzed the effect of Ca2+-calmodulin on membrane integration of tail-anchored proteins. ► We found that Ca2+-calmodulin inhibits membrane insertion of TA proteins. ► This inhibition was prevented by trifluoperazine, a CaM antagonist. ► The effect of Ca2+-CaM was also seen for a purified TA protein. Ca2+-CaM can be cross-linked to TA proteins.