15.8:
Insertion of Single-pass Transmembrane Proteins in the RER
The ER signal sequence of a transmembrane protein acts as a start-transfer signal for translocation through the Sec61 channel on the ER membrane.
As translocation continues, the looped signal sequence uses the lateral gate of the Sec61 channel to move out.
It is then cleaved off by the adjacent signal peptidase complex, releasing the N terminal into the lumen.
A hydrophobic domain in the polypeptide chain cannot cross the lipid bilayer and acts as a stop-transfer signal.
Therefore, when the Sec61 channel encounters such a domain, it opens laterally to release the hydrophobic domain into the lipid bilayer, forming a transmembrane domain.
The ribosome then continues the synthesis of the cytosolic domain.
After translation terminates, the dissociating ribosome leaves behind a type I signal transmembrane protein embedded in the ER membrane with its N terminal in the lumen and C terminal in the cytosol.
If the hydrophobic domain is preceded by positively charged residues, the N terminal remains out in the cytosol.
The resultant transmembrane protein, a type II protein, is an upside-down type I protein.
15.8:
Insertion of Single-pass Transmembrane Proteins in the RER
Integral membrane proteins are proteins adhered to the lipid bilayer of a cell organelle or membrane. They can be of two types: transmembrane integral proteins that span the lipid bilayer and monotopic proteins that are attached to either side of the membrane but do not pass through it.
Integral transmembrane proteins possess transmembrane and extra membrane domains. The transmembrane domains are primarily made of 20-25 hydrophobic amino acids arranged in a helical secondary confirmation. These domains are stable enough to be embedded in the phospholipid interior of the membrane and are critical in determining the protein's topology. Such proteins are inserted into the ER membrane co-translationally and are broadly categorized as single-pass and multipass transmembrane proteins. There are three types of single-pass transmembrane proteins with a single domain traversing through the membrane.
Type I membrane proteins have a cleavable ER-signal sequence, a single transmembrane domain, the N terminal placed in the ER lumen. It has two distinct sequences to start and stop the polypeptide transfer through the translocon on the ER membrane. The human growth hormone receptor is a type I transmembrane protein.
Type II membrane proteins also have a single transmembrane domain, but it acts as a non-cleavable signal sequence and a membrane anchor, unlike type I membrane proteins. The transmembrane domain of the type II proteins is also called the signal anchor sequence. This sequence is always preceded by positive amino acid residues that prevent the N terminal of the polypeptide chain from slipping down into the translocon. Hence, the C terminal of type II proteins is oriented inside the ER lumen. The transferrin receptor and the Golgi galactosyltransferase are examples of a type II membrane protein.
Type III membrane proteins are similar to type II proteins in terms of the transmembrane domain structure; however, the positive amino acid residues are placed after the signal-anchor sequence. Thus, their N terminal is inserted into the translocon, and the C terminal is left out in the cytosol. Cytochrome P40 is a type III membrane protein.
Suggested Reading
- Guna, Alina, and Ramanujan S. Hegde. "Transmembrane domain recognition during membrane protein biogenesis and quality control." Current Biology 28, no. 8 (2018): R498-R511.
- Spiess, Martin, Tina Junne, and Marco Janoschke. "Membrane protein integration and topogenesis at the ER." The protein journal 38, no. 3 (2019): 306-316.