A sizable fraction of proteins destined for ER are first synthesized in the cell cytosol and then transported across the ER membrane–a process called post-translational translocation. Similar to cotranslationally translocated proteins, these proteins also use the Sec translocon complex to enter the ER lumen.

Targeting proteins to the ER

Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal sequence present on the target proteins available for interaction with the recognition site on the Sec61 channel.

The ER signal sequence of proteins translocating post-translation has characteristic features that distinguish them from cotranslationally translocated proteins. For example, in yeast, the signal sequence of post-translationally translocated proteins is relatively less hydrophobic compared to the signal sequence of cotranslationally translocating proteins. In contrast, in mammalian systems, the target proteins have a characteristic short positively charged N-terminal.

Translocon partners for post-translational translocation

All proteins enter the ER lumen using the Sec61 channel but the channel partners vary depending on whether it is a cotranslational or a post-translational translocation process. Sec62 and Sec63 play an important role during post-translational translocation. Sec62 has a strong affinity for the ER signal sequence present on the cytosol-translated proteins, while Sec63 has a specialized domain that hydrolyzes the ATP to allow the BiP chaperone to bind to the incoming protein. BiP chaperone is a lumenal chaperone that keeps the protein loosely folded or unfolded till it has attained the appropriate secondary structure. Together, the Sec62/63 complex and the BiP chaperone are involved in actively pulling the protein into the ER lumen by a Brownian ratcheting mechanism.

Other functions of the Sec proteins

Besides their central role in translocating proteins, Sec proteins are essential in other cell functions and diseases. For example, Sec62 is involved in the stress recovery of cells, while the Sec61 channel can double up as a passive ER calcium leak channel. Additionally, mutations and overexpression of the SEC genes are linked to diabetes, cancer, and various kidney and liver disorders in humans.