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.