Chasing the right tail: How the ER membrane complex recognizes its substrates

Abstract

Tail-anchored proteins are tethered to membranes of the ER, mitochondria, and peroxisomes. In this issue, Pleiner and colleagues (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202212007) show that the ER membrane complex (EMC) uses an inbuilt charge-dependent selectivity filter to specifically insert ER tail-anchored proteins according to their topology signals and to prevent the misincorporation of mitochondrial proteins.

Figure 1.

The features of C-terminal sequences direct TA proteins to their correct intracellular target membrane using a selectivity filter of the EMC in the ER membrane. (A) The properties of the C-terminal membrane anchors and the short subsequent sequences serve as targeting signals for TA proteins. The membrane integration of TA proteins of the yeast and human mitochondrial outer membrane is facilitated by Mim1 and MTCH2, respectively (7, 8). (B) The EMC complex promotes the translocation of negatively charged protein segments across the ER membrane, using their affinity to two arginine residues in EMC3. These positive charges serve as a selectivity filter to repel TA proteins with positive charges in their tail, preventing the mis-insertion of TA proteins destined for mitochondria and peroxisomes.