Figure 2.

Variations of polytopic protein topogenesis. (A) Simplest cotranslational topogenesis model in which ER targeting begins as signal recognition particle (SRP) recognizes an emerging signal sequence (TM), binds its receptor (SR) at the ER membrane, and transfers the RNC to the Sec61 translocon. TM topology is achieved through alternating signal and stop transfer activities that sequentially open and close the translocon pore. Careful orchestration of ribosome translocon junction ensures delivery of soluble domains into either cytosol or ER lumen and integration of TMs into the bilayer. (B) For CFTR, topology of TM1 and TM2 is established by two alternate pathways in which translocation is initiated by either TM1 (left) or TM2 (right). Most CFTR nascent chains utilized a posttranslational mechanism in which TM2 insertion drags TM1 into the translocon. (C) The short loop between TM3 and TM4 (five residues) suggests that TM3 and TM4 simultaneously insert into the translocon as a helical hairpin. A similar mechanism is also proposed for TM5-6, TM9-10, and TM11-12. (D) Stop transfer activity of TM8 is weakened by Asp924 which results in transient exposure of TM8 in the ER lumen before acquiring its final membrane spanning topology.