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: The orientation of Nin-Cout (type II) TMDs can be influenced by the positioning of positively charged flanking residues and the length of the N-terminal flanking region (von Heijne, 1989; Kocik et al., 2012). In line with these findings, the 6-aa N-terminus is a highly conserved region in NA and includes a positively charged residue (K or, less commonly, R) adjacent to the TMD (Figure 7A). To investigate whether these N-terminal features aid the marginally hydrophobic NA TMD inversion, we examined the glycosylation pattern of the TM∆G +1.3NA76aa construct with several N-terminal deletions and mutations (Figure 7B).