Tail-anchored proteins are a distinct class of integral membrane proteins located in several eukaryotic organelles, where they perform a diverse range of functions. These proteins have in common the C-terminal location of their transmembrane anchor and the resulting post-translational nature of their membrane insertion, which, unlike the co-translational membrane insertion of most other proteins, is not coupled to ongoing protein synthesis. The study of tail-anchored proteins has provided a paradigm for understanding the components and pathways that mediate post-translational biogenesis of membrane proteins at the endoplasmic reticulum. In this Commentary, we review recent studies that have converged at a consensus regarding the molecular mechanisms that underlie this process--namely, that multiple pathways underlie the biogenesis of tail-anchored proteins at the endoplasmic reticulum.
