Molecular code for protein insertion in the endoplasmic reticulum membrane is similar for N in –C out and N out –C in transmembrane helices

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Abstract
Transmembrane alpha-helices in integral membrane proteins can have two orientations in the membrane: N-in-C-out or N-out-C-in. Previous studies of model N-out-C-in transmembrane segment have led to a detailed, quantitative picture of the "molecular code" that relates amino acid sequence to membrane insertion efficiency in vivo [Hessa T, et al. (2007) Molecular code for transmembrane helix recognition by the Sec61 translocon. Nature 450:1026-1030], but whether the same code applies also to N-in-C-out transmembrane helices is unknown. Here, we show that the contributions of individual amino acids to the overall efficiency of membrane insertion are similar for the two kinds of helices and that the threshold hydrophobicity for membrane insertion can be up to approximate to 1 kcal/mol lower for N-in-C-out compared with N-out-C-in transmembrane helices, depending on the neighboring helices.