Type II transmembrane domain hydrophobicity dictates the cotranslational dependence for inversion.
Bottom Line: This places stringent hydrophobicity requirements on transmembrane domains (TMDs) from single-spanning membrane proteins.On examining the single-spanning influenza A membrane proteins, we found that the strict hydrophobicity requirement applies to the N(out)-C(in) HA and M2 TMDs but not the N(in)-C(out) TMDs from the type II membrane protein neuraminidase (NA).To investigate this discrepancy, we analyzed NA TMDs of varying hydrophobicity, followed by increasing polypeptide lengths, in mammalian cells and ER microsomes.
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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).