Self-association of transmembrane α-helices in model membranes: Importance of helix orientation and role of hydrophobic mismatch

Emma Sparr*, Walter L. Ash, Petr V. Nazarov, Dirk T.S. Rijkers, Marcus A. Hemminga, D. Peter Tieleman, J. Antoinette Killian

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

114 Citations (Scopus)


Interactions between transmembrane helices play a key role in almost all cellular processes involving membrane proteins. We have investigated helix-helix interactions in lipid bilayers with synthetic tryptophan-flanked peptides that mimic the membrane spanning parts of membrane proteins. The peptides were functionalized with pyrene to allow the self-association of the helices to be monitored by pyrene fluorescence and Trp-pyrene fluorescence resonance energy transfer (FRET). Specific labeling of peptides at either their N or C terminus has shown that helix-helix association occurs almost exclusively between antiparallel helices. Furthermore, computer modeling suggested that antiparallel association arises primarily from the electrostatic interactions between α-helix backbone atoms. We propose that such interactions may provide a force for the preferentially antiparallel association of helices in polytopic membrane proteins. Helix-helix association was also found to depend on the lipid environment. In bilayers of dioleoylphosphatidylcholine, in which the hydrophobic length of the peptides approximately matched the bilayer thickness, association between the helices was found to require peptide/lipid ratios exceeding 1/25. Self-association of the helices was promoted by either increasing or decreasing the bilayer thickness, and by adding cholesterol. These results indicate that helix-helix association in membrane proteins can be promoted by unfavorable protein-lipid interactions.

Original languageEnglish
Pages (from-to)39324-39331
Number of pages8
JournalJournal of Biological Chemistry
Issue number47
Publication statusPublished - 25 Nov 2005
Externally publishedYes


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