The translocon (also known as a translocator or translocation channel) is a complex of

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

s associated with the translocation of

polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...

s across membranes. In

eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...

s the term translocon most commonly refers to the complex that transports nascent

s with a targeting signal sequence into the interior (cisternal or lumenal) space of the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

(ER) from the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

. This translocation process requires the protein to cross a

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...

lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...

. The same complex is also used to integrate nascent

s into the membrane itself (

membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...

s). In

prokaryote A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...

s, a similar protein complex transports polypeptides across the (inner) plasma membrane or integrates membrane proteins. In either case, the protein complex are formed from Sec proteins (Sec: secretory), with the hetrotrimeric

Sec61 Sec61, termed SecYEG in prokaryotes, is a membrane protein complex found in all domains of life. As the core component of the translocon, it transports proteins to the endoplasmic reticulum in eukaryotes and out of the cell in prokaryotes. It is ...

being the channel. In prokaryotes, the homologous channel complex is known as SecYEG. This article focuses on the cell's native translocons, but

pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...

s can also assemble other translocons in their host membranes, allowing them to export

virulence factor Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the following ...

s into their target cells.

Central channel

The translocation channel is a hetero-trimeric protein complex called SecYEG in prokaryotes and

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 Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...

. 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 The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

. 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 bacteria, SecYEG forms a complex with SecDF, YajC and YidC. In eukaryotes, Sec61 forms a complex with the

oligosaccharyl transferase Oligosaccharyltransferase or OST () is a membrane protein complex that transfers a 14-sugar oligosaccharide from dolichol to nascent protein. It is a type of glycosyltransferase. The sugar Glc3Man9GlcNAc2 (where Glc=Glucose, Man=Mannose, and Gl ...

complex, the TRAP complex, and the membrane protein TRAM (possible chaperone). For further components, such as

signal peptidase Signal peptidases are enzymes that convert secretory and some membrane proteins to their mature or pro forms by cleaving their signal peptides from their N-termini. Signal peptidases were initially observed in endoplasmic reticulum (ER)-der ...

complex and the

SRP receptor Signal recognition particle (SRP) receptor, also called the docking protein, is a dimer composed of 2 different subunits that are associated exclusively with the rough ER in mammalian cells. Its main function is to identify the SRP units. SRP (s ...

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 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 The SecA protein is a cell membrane associated subunit of the eubacterial Sec or Type II secretory pathway, a system which is responsible for the secretion of proteins through the cell membrane. Within this system the SecA ATPase forms a transloc ...

ATPase.

Co-translational

In co-translational translocation, the translocon associates with the

ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...

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 In the philosophy of thermal and statistical physics, the Brownian ratchet or Feynman–Smoluchowski ratchet is an apparent perpetual motion machine of the second kind (converting thermal energy into mechanical work), first analysed in 1912 as a ...

. 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 The signal recognition particle (SRP) is an abundant, cytosolic, universally conserved ribonucleoprotein (protein-RNA complex) that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane ...

(SRP), which halts

translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...

of the polypeptide by the

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 A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bi ...

. 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

In eukaryotes, post-translational translocation depends on BiP and other complexes, including the

SEC62 Translocation protein SEC62 is a protein that in humans is encoded by the ''SEC62'' gene. Function The Sec61 complex is the central component of the protein translocation apparatus of the endoplasmic reticulum (ER) membrane. The protein encode ...

SEC63 Translocation protein SEC63 homolog is a protein that in humans is encoded by the ''SEC63'' gene. Function The Sec61 complex is the central component of the protein translocation apparatus of the endoplasmic reticulum (ER) membrane. The protein ...

integral membrane protein An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a signi ...

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

, 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

proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by w ...

s) from the cisternal space of the endoplasmic reticulum to the cytosol. ER-proteins are degraded in the

by the 26S

, a process known as

endoplasmic-reticulum-associated protein degradation Endoplasmic-reticulum-associated protein degradation (ERAD) designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the prote ...

, 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.

References