Membrane Insertion of Tail-Anchored Proteins.

Tail-anchored (TA) proteins are a heterogeneous group of transmembrane proteins with diverse important functions that share an unusual mechanism of insertion into their target membranes. Indeed, because of the C-terminal position of their transmembrane domain they do not have a chance to interact cotranslationally with Signal Recognition Particle and are thus delivered posttranslationally to the ER, to the outer mitochondrial- or to the peroxisomal membrane (as well as to the chloroplast outer envelope in plants). The subsequent insertion involves translocation of the C-terminus, however, TA proteins do not rely on the classical Sec61 translocon nor on the TOM machinery for their integration into the ER and outer mitochondrial membrane respectively. Recent work has demonstrated the existence of different biogenetic pathways for TA proteins. Notably, some are able to efficiently translocate their C-terminus across protein-free bilayers without the participation of any membrane or cytosolic protein, while others require assistance from cytosolic chaperons and membrane receptors. Whether or not assistance is required depends on features of the transmembrane domain. Several intriguing issues in TA protein biogenesis remain to be resolved and will undoubtedly be actively investigated in the coming years. These include the molecular characterization of the ER membrane receptors involved in the assisted pathway and the mechanism by which TA proteins discriminate between the outer mitochondrial membrane and the ER.