Cotranslational protein transport

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As cotranslational protein transport or cotranslational translocation in which is cell biology , a process referred to, in which already during the translation of the forming polypeptide chain of a protein into or through a biological membrane is transported. A distinction is made between this and a process called post-translational protein transport , with which the fully formed protein is only transported after translation.

Occurrence

In eukaryotes , cotranslational protein transport occurs primarily during transport through or into the membrane of the endoplasmic reticulum (ER). Through vesicle transport , the membrane-bound proteins can distribute themselves into the membranes of other organelles or into the cytoplasmic membrane via the secretory path . For this reason, the ribosomes attached to the ER membrane give the rough ER its name.

In prokaryotes , cotranslational protein transport occurs on the cytoplasmic membrane.

mechanism

Model of cotranslational protein transport across the ER membrane in mammalian cells

The transport process begins with the specific recognition of the N-terminal signal sequence . Once it appears on the surface of the ribosome, it is the signal recognition particle ( signal recognition particle bound SRP), which in the mammalian proteins of six and a 7SL RNA consists. The bound SRP interacts not only with the signal sequence, but also with the ribosome, whereby the synthesis rate of the nascent polypeptide chain is reduced. SRP is thus able to target the ribosome to the ER membrane without completing the protein to be transported beforehand. Once at the ER membrane, the complex of ribosome, nascent peptide chain and SRP interacts with the membrane in two ways. On the one hand, the SRP is bound by its membrane-bound receptor (SRP receptor), and on the other hand, the ribosome interacts directly with the tunnel-forming Sec61 complex (in mammals consisting of Sec61A1 , Sec61B and Sec61G ). After the SRP and the SRP receptor have bound to each other, the SRP detaches from the ribosome under GTP hydrolysis and transfers the nascent polypeptide chain to the actual translocation apparatus. The exact processes are still the subject of research.

In the mammalian system , reconstitution experiments have shown that, in addition to the SRP receptor, only two other components are required in the membrane to cotranslationally transport proteins in vitro . These are the TRAM protein ( translocating chain-associated membrane protein ) and the heterotrimeric Sec61 complex . Cross-linking experiments and electron microscopic studies showed that the Sec61 complex forms the channel through which the proteins are transported. The channel is formed by three to four heterotrimeric Sec61 complexes, which appear as a ring-shaped structure in the electron microscope image.

The insertion of the nascent chain into the translocation channel takes place in two steps. At the beginning of the translocation process, the bond between the Sec61 complex and the ribosome is relatively weak. The ribosomes can be washed off the membrane by a high salt treatment. Only when the nascent chain has reached a length of approx. 70 amino acids and a functional signal sequence is present does the bond between the ribosome and Sec61 complex increase - even under high salt conditions, ribosomes do not detach from the membrane. At the same time, the translocation channel opens to the luminal side of the ER. Electron microscope images showed that the ribosome sits on the membrane pore in such a way that the Sec61 channel represents an extension of the ribosome channel. The GTP-dependent synthesis of the nascent chain on the ribosome is sufficient as the sole force to transport the nascent polypeptide chain into the lumen of the ER.

  1. The signal sequence of the growing polypeptide chain is recognized and bound by the SRP. At the same time, the SRP also interacts with the ribosome, causing elongation arrest.
  2. The complex of ribosome, nascent polypeptide chain and SRP binds to the ER membrane on the Sec61 complex, this binding is mediated by a membrane-based SRP receptor.
  3. After GTP hydrolysis, SRP detaches from the ribosome, which is transferred to the Sec61 complex. A second signal sequence recognition step is carried out by the Sec61 complex.
  4. The translocation channel opens to the ER lumen. The N-terminus of the nascent chain is in a hairpin conformation, with one part of the loop being formed by the signal sequence and the other part by the C-terminal sections of the polypeptide chain. The signal sequence interacts with Sec61a, TRAM and membrane lipids. The further elongation of the polypeptide chain pushes the C-terminal area of ​​the loop through the membrane. The signal sequence is split off from the rest of the protein by the signal peptidase complex (SP complex).
  5. The remaining nascent polypeptide chain is then transported directly into the lumen of the ER through the channel formed by the ribosome and Sec61 complex.

literature