Polar/Ionizable residues in transmembrane segments: effects on helix-helix packing

PLoS One. 2012;7(9):e44263. doi: 10.1371/journal.pone.0044263. Epub 2012 Sep 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry*
  • Calcium-Transporting ATPases / chemistry
  • Cell Membrane / chemistry*
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Escherichia coli / cytology
  • Escherichia coli / metabolism
  • Glycophorins / chemistry
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / metabolism
  • Membrane Proteins / chemistry*
  • Micelles
  • Microsomes / drug effects
  • Microsomes / metabolism
  • Protein Multimerization / drug effects
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sodium Dodecyl Sulfate / pharmacology
  • Thermodynamics


  • Amino Acids
  • Glycophorins
  • Membrane Proteins
  • Micelles
  • Sodium Dodecyl Sulfate
  • Calcium-Transporting ATPases

Grants and funding

This work was supported by grants BFU2009-08401 (to IM) and BFU2010-19310 (to MAM-R) from the Spanish Ministry of Science and Innovation (MICINN, ERDF supported by the European Union), as well as by PROMETEO/2010/005 (to IM) from the Generalitat Valenciana. MB-P and CB-D were recipients of FPU and FPI predoctoral fellowships from the MICINN, respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.