# Translocon

The translocon (also known as a translocator or translocation channel) is a complex of proteins associated with the translocation of polypeptides across membranes. In eukaryotes the term translocon most commonly refers to the complex that transports nascent polypeptides with a targeting signal sequence into the interior (cisternal or lumenal) space of the endoplasmic reticulum (ER) from the cytosol. This translocation process requires the protein to cross a hydrophobic lipid bilayer. The same complex is also used to integrate nascent proteins into the membrane itself (membrane proteins). In prokaryotes, a similar protein complex transports polypeptides across the (inner) plasma membrane or integrates membrane proteins. In either case, the protein complex is formed from Sec proteins (Sec: secretory), with the hetero-trimeric Sec61 being the channel. In prokaryotes, the homologous channel complex is known as SecYEG.
This article focuses on the cell's native translocons, but pathogens can also assemble other translocons in their host membranes, allowing them to export virulence factors into their target cells.

## Central channel

The translocon channel is a hetero-trimeric protein complex called SecYEG in prokaryotes and Sec61 in eukaryotes. It consists of the subunits SecY, SecE, and SecG. The structure of this channel, in its idle state, has been solved by X-ray crystallography in archaea. SecY is the large pore subunit. A larger heptameric complex that includes the core trimeric protein and a tetramer is responsible for the transportation of a subset of polypeptides into the endoplasmic reticulum. The distinct features of the channel contribute to its function in the ER membrane. In a side view, the channel has an hourglass shape, with a funnel on each side. The extracellular funnel has a little "plug" formed out of an alpha-helix. In the middle of the membrane is a construction, formed from a pore ring of six hydrophobic amino acids that project their side chains inwards. This ensures selectivity of elements entering the channel. During protein translocation, the plug is moved out of the way, and a polypeptide chain is moved from the cytoplasmic funnel, through the pore ring, the extracellular funnel, into the extracellular space. Hydrophobic segments of membrane proteins exit sideways through the lateral gate into the lipid phase and become membrane-spanning segments.
In bacteria, SecYEG forms a complex with SecDF, YajC and YidC. In eukaryotes, Sec61 forms a complex with the oligosaccharyl transferase complex, the TRAP complex, and the membrane protein TRAM (possible chaperone). For further components, such as signal peptidase complex and the SRP receptor it is not clear to what extent they only associate transiently to the translocon complex.

## Translocation

The channel allows peptides to move in either direction, so additional systems in the translocon are required to move the peptide in a specific direction. There are two types of translocation: co-translational translocation (occurs concurrently with translation), and post-translational translocation (happens after translation). Each is seen in eukaryotes and bacteria. While eukaryotes unfold the protein with BiP and use other complexes to transport the peptide, bacteria use the SecA ATPase.

### Co-translational translocation (CTT)

In co-translational translocation, the translocon associates with the ribosome so that a growing nascent polypeptide chain is moved from the ribosome tunnel into the translocon channel. The co-translational translocation process in eukaryotes involves SRP that guide nascent polypeptide chains to the translocon while they are still associated with the ribosome. The translocon (translocator) acts as a channel through the hydrophobic membrane of the endoplasmic reticulum (after the SRP has dissociated and translation is continued). The emerging polypeptide is threaded through the channel as an unfolded string of amino acids, potentially driven by a Brownian Ratchet. Once translation has been completed, a signal peptidase cleaves off the short signal peptide from the nascent protein, leaving the polypeptide free in the interior of the endoplasmic reticulum.
In eukaryotes, proteins due to be translocated to the endoplasmic reticulum are recognized by the signal-recognition particle (SRP), which halts translation of the polypeptide by the ribosome while it attaches the ribosome to the SRP receptor on the endoplasmic reticulum. This recognition event is based upon a specific N-terminal signal sequence that is in the first few codons of the polypeptide to be synthesised. Bacteria also use an SRP, together with a chaperone YidC that is similar to the eukaryote TRAM.
The translocon can also translocate and integrate membrane proteins in the correct orientation into the membrane of the endoplasmic reticulum. The mechanism of this process is not fully understood but involves the recognition and processing by the translocon of hydrophobic stretches in the amino acid sequence, which are destined to become transmembrane helices. Closed by stop-transfer sequences and opened by embedded signal sequences, the plug alters between its open and closed states to place helices in different orientations.

### Post-translational translocation (PTT)

In eukaryotes, post-translational translocation depends on BiP and other complexes, including the SEC62/SEC63 integral membrane protein complex. In this mode of translocation, Sec63 helps BiP hydrolyze ATP, which then binds to the peptide and "pulls" it out. This process is repeated for other BiP molecules until the entire peptide has been pulled through.
In bacteria, the same process is done by a "pushing" ATPase known as SecA, sometimes assisted by the SecDF complex on the other side responsible for pulling. The SecA ATPase uses a "push-and-slide" mechanism to move a polypeptide through the channel. In the ATP-bound state, SecA interacts through a two-helix finger with a subset of amino acids in a substrate, pushing them (with ATP hydrolysis) into the channel. The interaction is then weakened as SecA enters the ADP-bound state, allowing the polypeptide chain to slide passively in either direction. SecA then grabs a further section of the peptide to repeat the process.

## The ER-retrotranslocon

Translocators can also move polypeptides (such as damaged proteins targeted for proteasomes) from the cisternal space of the endoplasmic reticulum to the cytosol. ER-proteins are degraded in the cytosol by the 26S proteasome, a process known as endoplasmic-reticulum-associated protein degradation, and therefore have to be transported by an appropriate channel. This retrotranslocon is still enigmatic.
It was initially believed that the Sec61 channel is responsible for this retrograde transport, implying that transport through Sec61 is not always unidirectional but also can be bidirectional. However, the structure of Sec61 does not support this view and several different proteins have been suggested to be responsible for transport from the ER lumen into the cytosol.

## Translocon quality control (TQC)

Translocons can be clogged by translationally stalled or improperly folded proteins engaging with the complex. This is one of the ways translocons can become dysfunctional; for example in co-translational translocation (CTT), translocon clogging can occur due to translationally stalled ER-targeted proteins. Translocon clogging during post-translational translocation (PTT) may happen when proteins are not properly folded or form aggregates before they are fully translocated.
Translocon quality control mechanisms in the cell restore translocon function by relieving clogged translocon channels during protein translocation. The ubiquitin proteasome system (UPS) is one of multiple degradation mechanisms under TQC. The process includes clogged protein targeting by the attachment of ubiquitin enzymes for degradation by the proteasome.