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Nucleic Acids Research, 2003, Vol. 31, No. 2 556-561
© 2003 Oxford University Press

Cellular uptake of Antennapedia Penetratin peptides is a two-step process in which phase transfer precedes a tryptophan-dependent translocation

Geneviève Dom, Chloë Shaw-Jackson, Christelle Matis, Olivier Bouffioux1, Jacques J. Picard, Alain Prochiantz2, Marie-Paule Mingeot-Leclercq3, Robert Brasseur1 and René Rezsohazy*

Unit of Developmental Genetics, Université Catholique de Louvain, 73 (boîte 82) avenue Mounier, 1200 Brussels, Belgium, 1 Centre de Biophysique Moléculaire Numérique, Faculté Universitaire des Sciences Agronomiques de Gembloux, 2 passage des déportés, 5030 Gembloux, Belgium, 2 CNRS UMR 8542, Ecole Normale Supérieure, 46 rue d‘Ulm, 75230 Paris Cedex 05, France and 3 Unit of Cellular and Molecular Pharmacology, Université Catholique de Louvain, 73 (boîte 70) avenue Mounier, 1200 Brussels, Belgium

*To whom correspondence should be addressed. Tel: +32 2 764 7383; Fax: +32 2 764 7385; Email: rene.rezsohazy{at}gede.ucl.ac.be

Several homeodomains and homeodomain-containing proteins enter live cells through a receptor- and energy-independent mechanism. Translocation through biological membranes is conferred by the third {alpha}-helix of the homeodomain, also known as Penetratin. Biophysical studies demonstrate that entry of Penetratin into cells requires its binding to surface lipids but that binding and translocation are differentially affected by modifications of some physico-chemical properties of the peptide, like helical amphipathicity or net charge. This suggests that the plasma membrane lipid composition affects the internalization of Penetratin and that internalization requires both lipid binding and other specific properties. Using a phase transfer assay, it is shown that negatively charged lipids promote the transfer of Penetratin from a hydrophilic into a hydrophobic environment, probably through charge neutralization. Accordingly, transfer into a hydrophobic milieu can also be obtained in the absence of negatively charged lipids, by the addition of DNA oligonucleotides. Strikingly, phase transfer by charge neutralization was also observed with a variant peptide of same charge and hydrophobicity in which the tryptophan at position 6 was replaced by a phenylalanine. However, Penetratin, but not its mutant version, is internalized by live cells. This underscores that charge neutralization and phase transfer represent only a first step in the internalization process and that further crossing of a biological membrane necessitates the critical tryptophan residue at position 6.


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