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Transmembrane Peptides Stabilize Inverted Cubic Phases in a Biphasic Length-Dependent Manner: Implications for Protein-Induced Membrane Fusion

D. P. Siegel ^*, V. Cherezov , D. V. Greathouse , R. E. Koeppe, II , J. Antoinette Killian  and M. Caffrey  ^¶ **

^* Givaudan Inc., Cincinnati, Ohio; Department of Chemistry, The Ohio State University, Columbus, Ohio; Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas; Department of Biochemistry of Membranes, University of Utrecht, Utrecht, The Netherlands; ^¶ Biochemistry and Biophysics Programs, The Ohio State University, Columbus, Ohio; and ^** College of Science, University of Limerick, Limerick, Ireland

Correspondence: Address reprint requests to David P. Siegel, Givaudan Inc., 1199 Edison Drive, Cincinnati, OH 45215. Tel.: 513-948-4840; E-mail: david.siegel{at}givaudan.com.

WALP peptides consist of repeating alanine-leucine sequences of different lengths, flanked with tryptophan "anchors" at each end. They form membrane-spanning -helices in lipid membranes, and mimic protein transmembrane domains. WALP peptides of increasing length, from 19 to 31 amino acids, were incorporated into N-monomethylated dioleoylphosphatidylethanolamine (DOPE-Me) at concentrations up to 0.5 mol % peptide. When pure DOPE-Me is heated slowly, the lamellar liquid crystalline (L) phase first forms an inverted cubic (Q_II) phase, and the inverted hexagonal (H_II) phase at higher temperatures. Using time-resolved x-ray diffraction and slow temperature scans (1.5°C/h), WALP peptides were shown to decrease the temperatures of Q_II and H_II phase formation (T_Q and T_H, respectively) as a function of peptide concentration. The shortest and longest peptides reduced T_Q the most, whereas intermediate lengths had weaker effects. These findings are relevant to membrane fusion because the first step in the L/Q_II phase transition is believed to be the formation of fusion pores between pure lipid membranes. These results imply that physiologically relevant concentrations of these peptides could increase the susceptibility of biomembrane lipids to fusion through an effect on lipid phase behavior, and may explain one role of the membrane-spanning domains in the proteins that mediate membrane fusion.