Type II transmembrane domain hydrophobicity dictates the cotranslational dependence for inversion.
Bottom Line: Membrane insertion by the Sec61 translocon in the endoplasmic reticulum (ER) is highly dependent on hydrophobicity.Overall the cotranslational inversion of marginally hydrophobic NA TMDs initiates once ~70 amino acids past the TMD are synthesized, and the efficiency reaches 50% by ~100 amino acids, consistent with the positioning of this TMD class in type II human membrane proteins.Inversion of the M2 TMD, achieved by elongating its C-terminus, underscores the contribution of cotranslational synthesis to TMD inversion.
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Mentions: Our results thus far indicate that full-length NA with a marginally hydrophobic TMD localizes to the PM, likely because the longer C-tail facilitates inversion and potentially ER targeting. By making smaller increases in the C-tail length after the marginally hydrophobic NA TMD, we observed a stepwise increase in the average PM/IC ratios (Figure 4A). The increase slightly began with a C-tail length of 41 aa, which approximates the length of the ribosomal tunnel (Malkin and Rich, 1967; Blobel and Sabatini, 1970), and increased until a length of 76 aa, which showed a PM/IC profile distribution similar to the full-length construct (TM∆G +1.3NA440aa) in this steady-state assay. These results confirmed that the C-tail length contributes to PM localization of the marginally hydrophobic NA TMD.