Asn‐ and Asp‐mediated interactions between transmembrane helices during translocon‐mediated membrane protein assembly

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Abstract
Inter‐helix hydrogen bonding involving asparagine (Asn, N), glutamine (Gln, Q), aspartic acid (Asp, D) or glutamic acid (Glu, E) can drive efficient di‐ or trimerization of transmembrane helices in detergent micelles and lipid bilayers. Likewise, Asn–Asn and Asp–Asp pairs can promote the formation of helical hairpins during translocon‐mediated membrane protein assembly in the endoplasmic reticulum. By in vitro translation of model integral membrane protein constructs in the presence of rough microsomes, we show that Asn‐ or Asp‐mediated interactions with a neighbouring transmembrane helix can enhance the membrane insertion efficiency of a marginally hydrophobic transmembrane segment. Our observations suggest that inter‐helix hydrogen bonds can form during Sec61 translocon‐assisted insertion and thus could be important for membrane protein assembly.