After targeting, the SRP-SR complex rearranges into the prehandover configuration. The large size of the SRP-SR complex precludes the ribosome exit tunnel from approaching the membrane (see B), thereby allowing access to EMC without competition from Sec61. Release of the SA from SRP allows SA binding to the membrane and sampling of EMCs cytosolic vestibule by the N-tail. The SA can reach the membrane because a downstream tether of more than 25 aa has already been synthesized by this point. The EMC sampling step is transient and once the SRP-SR complex dissociates, the ribosome docks at Sec61, at which point access to EMC is restricted due to steric hinderance by the ribosome. If the SA was inserted during the EMC sampling step, the substrate achieves the Nexotopology. Otherwise, Sec61 can insert the SA in the Ncyttopology.
