pH-Activated fusogenic transmembrane LV-peptides.
LV-peptides mimic the in vitro fusogenicity of synthetic fusion protein transmembrane domains. The original versions of these peptides consist of a variable hydrophobic core (containing leucine and/or valine residues (LV)) that is flanked by invariant lysine triplets at both termini. Previously, peptide fusogenicity was correlated with the structural plasticity of their hydrophobic cores. Here, we examined the functional importance of positively charged flanking residues. To this end, we determined the fusogenicities of peptide variants that contain terminal His and/or Lys triplets. Interestingly, liposome fusion by peptides with His triplets was triggered by acidic pH. The pH dependence of fusion is reflected by a sigmoidal titration curve whose midpoint is close to the pKa value of histidine. Thus, only peptides with positively charged residues at both termini are fusogenic. The previously established dependence of fusogenicity on the sequence of the hydrophobic peptide core of Lys-flanked LV-peptides was preserved with the His-flanked versions at low pH. We propose that the structural flexibility of the core region as well as positive terminal charges are required for LV-peptide function in lipid mixing. In a potential practical application, the pH-dependent LV-peptides might prove to be useful in the lipofection of eukaryotic cells.
Hofmann
Mathias W
MW
Lehrstuhl Chemie der Biopolymere, Technische Universität München, Weihenstephaner Berg 3, 85354 Freising, Germany.
Poschner
Bernhard C
BC
Hauser
Stephanie
S
Langosch
Dieter
D
D000595:Amino Acid Sequence; D006639:Histidine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007930:Leucine / Q000737:chemistry*; D008051:Lipid Bilayers / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry; D008561:Membrane Fusion; D010455:Peptides / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D014633:Valine / Q000737:chemistry*
D008051:Lipid Bilayers; D010455:Peptides; D006639:Histidine; D007930:Leucine; D014633:Valine; D008239:Lysine