Translocon

The translocon (commonly 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. Bacterial pathogens can also assemble other translocons in their host membranes, allowing them to export virulence factors into their target cells. The translocon (commonly 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. Bacterial pathogens can also assemble other translocons in their host membranes, allowing them to export virulence factors into their target cells. In either case, the protein complex are formed from Sec proteins (Sec: secretory), with the hetrotrimeric Sec61 being the channel. In prokaryotes, the homologous channel complex is known as SecYEG. The translocation 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. 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. 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 E. coli, SecYEG complexes dimerize on the membrane. In eukaryotes, multiple copies of Sec61 come together and form a larger complex along with further components such as 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. 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 three types of translocation: cotranslational translocation that happens as translation happens, and two types of post-translational translocation that happens after translation, each 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. 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 SecY channel. 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 is finished, 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. 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.