TY - JOUR
T1 - Interaction of S413-PV cell penetrating peptide with model membranes
T2 - Relevance to peptide translocation across biological membranes
AU - Mano, Miguel
AU - Henriques, Ana
AU - Paiva, Artur
AU - Prieto, Manuel
AU - Gavilanes, Francisco
AU - Simões, Sérgio
AU - Pedroso de Lima, Maria C.
PY - 2007/5
Y1 - 2007/5
N2 - Cell penetrating peptides (CPPs) have been successfully used to mediate the intracellular delivery of a wide variety of molecules of pharmacological interest both in vitro and in vivo, although the mechanisms by which the cellular uptake occurs remain unclear and controversial. Following our previous work demonstrating that the cellular uptake of the S413-PV CPP occurs mainly through an endocytosis-independent mechanism, we performed a detailed biophysical characterization of the interaction of this peptide with model membranes. We demonstrate that the interactions of the S413-PV peptide with membranes are essentially of electrostatic nature. As a consequence of its interaction with negatively charged model membranes, the S413-PV peptide becomes buried into the lipid bilayer, which occurs concomitantly with significant peptide conformational changes that are consistent with the formation of a helical structure. Comparative studies using two related peptides demonstrate that the conformational changes and the extent of cell penetration are dependent on the peptide sequence, indicating that the helical structure acquired by the S413-PV peptide is relevant for its nonendocytic uptake. Overall, our data suggest that the cellular uptake of the S413-PV CPP is a consequence of its direct translocation through cell membranes, following conformational changes induced by peptide-membrane interactions.
AB - Cell penetrating peptides (CPPs) have been successfully used to mediate the intracellular delivery of a wide variety of molecules of pharmacological interest both in vitro and in vivo, although the mechanisms by which the cellular uptake occurs remain unclear and controversial. Following our previous work demonstrating that the cellular uptake of the S413-PV CPP occurs mainly through an endocytosis-independent mechanism, we performed a detailed biophysical characterization of the interaction of this peptide with model membranes. We demonstrate that the interactions of the S413-PV peptide with membranes are essentially of electrostatic nature. As a consequence of its interaction with negatively charged model membranes, the S413-PV peptide becomes buried into the lipid bilayer, which occurs concomitantly with significant peptide conformational changes that are consistent with the formation of a helical structure. Comparative studies using two related peptides demonstrate that the conformational changes and the extent of cell penetration are dependent on the peptide sequence, indicating that the helical structure acquired by the S413-PV peptide is relevant for its nonendocytic uptake. Overall, our data suggest that the cellular uptake of the S413-PV CPP is a consequence of its direct translocation through cell membranes, following conformational changes induced by peptide-membrane interactions.
KW - Amphipathic alpha helix
KW - Cell penetrating peptide
KW - Circular dichroism
KW - Peptide-membrane interaction
KW - Protein transduction domain
KW - Tryptophan fluorescence
UR - http://www.scopus.com/inward/record.url?scp=34248347468&partnerID=8YFLogxK
U2 - 10.1002/psc.842
DO - 10.1002/psc.842
M3 - Article
C2 - 17437249
AN - SCOPUS:34248347468
SN - 1075-2617
VL - 13
SP - 301
EP - 313
JO - JOURNAL OF PEPTIDE SCIENCE
JF - JOURNAL OF PEPTIDE SCIENCE
IS - 5
ER -