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Insertion of Multi-pass Transmembrane Proteins in the RER

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Multipass transmembrane proteins have two or more hydrophobic domains embedded across the ER membrane.

Consider a protein with three transmembrane domains. Its N-terminal ER signal sequence acts as the start-transfer cue for polypeptide translocation down the Sec61 channel. This signal sequence is later cleaved by the signal peptidase complex on the ER membrane.

Upon encountering a hydrophobic region, the translocon stops the polypeptide transfer and opens the lateral gate to transfer this domain into the lipid bilayer.

Then, the translation resumes, synthesizing a cytosolic domain until the next transmembrane domain is encountered.

Translocation pauses again for the membrane integration of this second transmembrane domain.

The above cycle repeats to incorporate the third transmembrane domain in the membrane.

After translation terminates, the resultant multipass protein has three transmembrane and four extra-membrane domains with its N-terminal in the ER lumen and the C-terminal in the cytosol.

Proteins with odd-numbered transmembrane domains orient their N and C termini on the opposite sides of the membrane, while proteins with even-numbered transmembrane domains align their termini on the same side.

Overview

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The rough ER membrane synthesizes, assembles, and embeds transmembrane proteins in diverse topologies. These proteins function as transporters or channels and can remain in the ER membrane or are sent to the Golgi complex, lysosome, and cell membrane.

The multipass transmembrane proteins are the type IV integral membrane proteins with multiple topogenic sequences determining their spatial arrangement in the ER membrane. Nearly all multipass proteins lack a cleavable signal sequence and use their first hydrophobic or transmembrane domain as the ER signal sequence. The positioning of positive residues before or after the first transmembrane domain determines the orientation of the N terminal of the protein in the cytosol or lumen, respectively.

The signal recognition particle (SRP) and its receptor (SR) are required to initiate the translocation of the first transmembrane domain of a multipass membrane protein through the ER membrane. The threading of subsequent transmembrane domains is independent of the SRP-SR complex. It is managed by the ribosome-translocon assembly and is primarily dependent on the hydrophobicity of the translated domain. The N-terminal of multipass proteins like glucose transporters and Sec61 lies in the cytosol, while that of G protein-coupled receptors are placed in the ER lumen.

The insertion of single-pass transmembrane proteins is understood better as compared to the multipass transmembrane proteins. The multipass proteins have complex biophysical and topological features affected by the length and hydrophobic profile of their transmembrane domains, the distance between consecutive transmembrane domains, and the length of the extra-membrane loops. The Sec61 translocon-ribosome assembly forms the core of protein translocation of membrane proteins. However, it is an overly simplified model to explain the incorporation of multipass proteins. Different accessory complexes like TRAP and TRAM interact with the Sec61 translocon and assist in accurate folding, insertion, and assembly of multipass transmembrane proteins.

Transcript

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