Abstract
The vast majority of membrane proteins are anchored to biological membranes through hydrophobic α-helices. Sequence analysis of high-resolution membrane protein structures show that ionizable amino acid residues are present in transmembrane (TM) helices, often with a functional and/or structural role. Here, using as scaffold the hydrophobic TM domain of the model membrane protein glycophorin A (GpA), we address the consequences of replacing specific residues by ionizable amino acids on TM helix insertion and packing, both in detergent micelles and in biological membranes. Our findings demonstrate that ionizable residues are stably inserted in hydrophobic environments, and tolerated in the dimerization process when oriented toward the lipid face, emphasizing the complexity of protein-lipid interactions in biological membranes.
Highlights
The vast majority of membrane proteins are anchored to biological membranes through hydrophobic a-helices
Our findings demonstrate that ionizable residues are stably inserted in hydrophobic environments, and tolerated in the dimerization process when oriented toward the lipid face, emphasizing the complexity of protein-lipids interactions in biological membranes
Ionizable amino acid residues in TM a-helices TM helices of lengths between 17 and 38 residues were selected from the MPTOPO database [20], which included helical segments that do completely span the hydrophobic core of the membrane
Summary
The vast majority of membrane proteins are anchored to biological membranes through hydrophobic a-helices. These transmembrane (TM) a-helices, rather than serving solely as featureless hydrophobic stretches required for anchorage of proteins in membranes, have structural and/or functional roles well beyond this canonical capacity. The folding and assembly of membrane proteins rely in part on interacting TM helices, which was conceptualized as a two-stage process [1]. TM helices are inserted into the membrane by the translocon. The driving force for this process derives primarily from the transfer of hydrophobic side chains from the aqueous channel of the translocon to the apolar region of the bilayer [2]. In the apolar environment of the membrane core, van der Waals packing, hydrogen bonding and ionic interactions are the dominant contributors to TM helix packing
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