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J. Biol. Chem., Vol. 280, Issue 47, 39324-39331, November 25, 2005

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Self-association of Transmembrane -Helices in Model Membranes

IMPORTANCE OF HELIX ORIENTATION AND ROLE OF HYDROPHOBIC MISMATCH^*

Emma Sparr1, Walter L. Ash2, Petr V. Nazarov¶, Dirk T. S. Rijkers||, Marcus A. Hemminga¶, D. Peter Tieleman3, and J. Antoinette Killian

From the Department of Biochemistry of Membranes, Institute of Biomembranes and Bijvoet Center for Biomolecular Research, and ^||Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Utrecht University, Padualaan 8, NL-3584 CH Utrecht, The Netherlands, the Department of Biological Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada, and the ^¶Laboratory of Biophysics Wageningen University, P. O. Box 8128, 6700 ET Wageningen, The Netherlands

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 -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.

Received for publication, March 15, 2005 , and in revised form, September 13, 2005.

^* This work was supported in part by the Canadian Institutes of Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table A.

³ Alberta Heritage Foundation for Medical Research Senior scholar, Canadian Institutes of Health Research New Investigator.

¹ Supported by The Swedish Foundation for International Cooperation in Research and Higher Education. To whom correspondence may be addressed. Present address: Physical Chemistry 1, Center for Chemistry and Chemical Engineering, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden. Tel.: 46-0-46-222-48-12; Fax: 46-0-46-222-44-13; E-mail: emma.sparr{at}fkem1.lu.se.

² Supported by an Alberta Heritage Foundation for Medical Research studentship and a National Sciences and Engineering Research Council Canada Graduate Scholarship. To whom correspondence may be addressed. Present address: Biological Sciences 405, 2500 University Drive NW, Calgary T2N 1N4, Canada. Tel.: 403-220-4039; Fax: 403-289-9311; E-mail: wlash{at}ucalgary.ca.

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