A comparison of the channel gating mechanisms for forward and ret-
rotranslocation at the ER. Top: A model for Sec61-mediated forward translocation
based on structural and biochemical studies on bacterial SecY . A monomeric
Sec61 complex forms a channel that is constricted at the center by a pore ring
formed by a collection of hydrophobic residues. A helix ‘plug’ further seals the channel from the luminal side. When a nascent polypeptide bearing a signal sequence is synthesized by the ribosome, the signal sequence is captured by the signal recognition particle (SRP), which brings the nascent chain-ribosome complex to the Sec61 channel via an ER-anchored SRP receptor. Nascent chain is inserted into the channel as a loop. The interaction of the signal sequence with the channel causes a
conformational change, resulting in the removal of the ‘plug’ and pore opening. Bottom: Hrd1-mediated retrotranslocation for ERAD-L substrates. Hrd1 forms a homooligomerized pore in the ER membrane. Substrate binding to Hrd1 in the lumen causes autoubiquitination of the RING domain in the cytosol, which in turn activates the channel and allows substrate to slip through the membrane. In cells, Hrd1 is assisted by cofactors that may coordinate substrate binding with channel activation.