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9 CONTENTS 0-8493-1141-1/02/$0.00+$1.50 © 2002 by CRC Press LLC Structure Prediction of CPPs and Iterative Development of Novel CPPs Olivier Bouffioux, Frédéric Basyn, René Rezsohazy, and Robert Brasseur 9.1 Introduction ..................................................................................................188 9.2 Methods........................................................................................................190 9.2.1 Description of Water–Bilayer Interfaces .........................................190 9.2.2 Atomic Surface Hydrophobicity (First Restraint)...........................191 9.2.3 Lipid Perturbation (Second Restraint).............................................193 9.2.4 Charge Simulation (Third Restraint) ...............................................194 9.2.5 Procedure..........................................................................................197 9.2.6 Monte Carlo Procedure....................................................................198 9.2.7 Pex2Dstat Files ................................................................................198 9.2.8 Molecular Hydrophobicity Potential (MHP)...................................199 9.3 Results ..........................................................................................................202 9.3.1 Efficiency of Monte Carlo Method Applied to Short Peptides and Membrane Proteins ...................................................................202 9.3.1.1 Hydrophobic Peptides.......................................................202 9.3.1.2 Membrane Proteins...........................................................204 9.3.2 Penetratin..........................................................................................206 9.3.2.1 Uncharged Membrane Model...........................................208 9.3.2.2 Charged Bilayer Model ....................................................210 9.4 Conclusions ..................................................................................................215 Acknowledgments..................................................................................................219 References..............................................................................................................219 187
188 Cell-Penetrating Peptides: Processes and Applications 9.1 INTRODUCTION Homeoproteins define a huge group of transcription factors sharing the evolutionary conserved homeodomain. 1 Representatives of this group of proteins are found in all the eukaryotic phyla, including yeasts, where they fulfill a wide range of biological functions. Among these functions, homeoproteins are involved in developmental processes such as the mating type switch in yeast, the main body axis patterning of animal embryos, limb development, regionalization of developing organs, and control of cell proliferation and differentiation. 2,3 With a few exceptions, the homeodomain is 60 amino acids long; the structure determination of several representatives has shown a globular fold made of two antiparallel α-helices followed by a third, perpendicular one. 3-6 In some instances, the third α-helix may be followed by a kink and a short, fourth α-helix. The wellrecognized function of the homeodomain is to bind DNA in a sequence-specific manner. Its third α-helix thus fits into the major groove of a cognate DNA site with amino acids contacting the base pairs. Furthermore, the extended N-terminal extremity of the homeodomain makes additional contacts within the DNA minor groove. The binding of the homeodomain to DNA also involves charge interactions, and basic residues in particular — namely, lysines and arginines — contribute by interacting with the phosphate groups of the DNA backbone. Recently, it appeared that the homeodomain contributes to various other functions. It has been shown that, at least in some instances, homeodomains can act as an RNA binding domain, 6 define a transcriptional activation or re<strong>press</strong>ion domain, 6-9 modulate the activity of the protein, 10,11 and take part in protein-to-protein interactions. 12-15 Among these new roles, the most unforeseen was an involvement in the intracellular trafficking of homeoproteins as well as in cell-to-cell communication. Prochiantz and collaborators reported that the Antennapedia homeoprotein can indeed be taken up by live cells. 16 Internalization by cells was further shown to be conferred by a 16 amino acid-long peptide corresponding to the third α-helix of the homeodomain. 17 Furthermore, this α-helix also appeared to allow the protein to be conveyed to the cell nucleus. Later on, the group of Prochiantz reported that the Engrailed homeoprotein can escape cells and that its commitment to the secretory pathway is provided by an 11-amino acid-long motif overlapping helices 2 and 3 of the homeodomain and corresponding to a functional nuclear export signal. 18,19 It was therefore proposed that the access of Engrailed to the secretory pathway may be conditioned by its transit to the nucleus. All these data strongly suggest that the homeodomain transcription factors may act as signaling molecules and play a paracrine function. However, the biological phenomena relying on this possible paracrine function remain to be identified. The ability of Antennapedia to be taken up by cells has now been extended to other homeoproteins 20,21 (Rezsohazy, unpublished data). Biophysical and cytological studies provided evidence that the cellular entry of homeoproteins, or of peptides corresponding to the third α-helix of their homeodomain now called penetratins, relies on a receptor- and energy-independent mechanism. 22 Indeed, penetratin can reach the intracellular milieu at either 37 or 4°C.
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CELL- PENETRATING PEPTIDES Processe
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Pharmacology and Toxicology: Basic
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Library of Congress Cataloging-in-P
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to the handbook are prominent resea
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REFERENCES 1. Green, M. and Loewens
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Contributors Mats Andersson Microbi
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Erin T. Pelkey Department of Chemis
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Contents Section I Classes of Cell-
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Chapter 16 Cell-Penetrating Peptide
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The Tat-Derived Cell-Penetrating Pe
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24 Cell-Penetrating Peptides: Proce
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3 Transportans Margus Pooga, Mattia
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Transportans 55 Indeed, galparan is
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Transportans 57 especially the endo
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Transportans 59 In the penetration
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Transportans 61 A 21-mer antisense
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Transportans 63 Commonly, the prote
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Transportans 65 antibiotin antibodi
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Transportans 67 For cross-linking o
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Transportans 69 and still retain ef
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Model Amphipathic Peptides 73 its D
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Model Amphipathic Peptides 75 pmol/
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TABLE 4.1 Internalization of Peptid
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TABLE 4.2 Internalization of Peptid
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Model Amphipathic Peptides 81 relat
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Model Amphipathic Peptides 87 A cat
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Model Amphipathic Peptides 89 At th
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Model Amphipathic Peptides 91 16. H
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Signal Sequence-Based Cell-Penetrat
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116 Cell-Penetrating Peptides: Proc
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Biophysical Studies of Cell-Penetra
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Toxicity and Side Effects of Cell-P
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Kinetics of Uptake of Cell-Penetrat
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Cell-Penetrating Peptide Conjugatio
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FIGURE 15.9 (Color Figure 15.9 foll
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Cell-Penetrating Peptides as Vector
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TABLE 16.1 Examples of Transport of
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CPP 2 Cargo or mRNA CAP Antisense A
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Microbial Membrane-Permeating Pepti
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Index A Abaecin, 129 Abz radiolabel
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Index 399 Diffraction, 168 Disulphi
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Index 401 structure prediction, 187
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Index 403 pRB proteins, Tat-E1A bin
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Index 405 lipid perturbation (secon
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