Effects of ‘hydrophobic mismatch’ on the location of transmembrane helices in the ER membrane

We have studied the effects of ‘hydrophobic mismatch’ between a poly‐Leu transmembrane helix (TMH) and the ER membrane using a glycosylation mapping approach. The simplest interpretation of our results is that the lumenal end of the TMH is located deeper in the membrane for both short (negative mismatch) and long (positive mismatch) TMHs than for poly‐Leu segments of intermediate length. We further find that the position‐specific effect of Lys residues on the location of short TMHs in the membrane varies with an apparent helical periodicity when the Lys residue is moved along the poly‐Leu stretch. We discuss these findings in the context of models for peptide–lipid interactions during hydrophobic mismatch.