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Signal Peptides 307 14.4.2.2 Specificity of Type I Signal Peptidases As noted above, signal peptides have a weak consensus pattern around their cleavage site known as the (–3, –1) rule. 153 Namely, the residues at positions –3 and –1 from the cleavage site are small (and neutral) such as alanine in most cases. In eukaryotes, this requirement is less stringent, allowing glycines and serines as well as alanines; it is more stringent in thylakoid membrane. 169,172,173 With experimental analyses, this rule was confirmed as the substrate specificity of type I signal peptidases. However, because the consensus pattern is so weak, many other potential consensus sites could be around the authentic site in a preprotein. More importantly, it seems difficult to discriminate signal-anchored proteins from proteins with cleavable signal peptides by mere existence of such a consensus pattern. 151 Several experiments show that the degree of hydrophobicity in h-region affects the cleavage. 174 For example, signal peptides become uncleavable when their hregion is artificially extended. 175 The three-dimensional structure of a catalytic Nterminal fragment of E. coli type I signal peptidase gives some hints on this enigma. 176,177 The structure shows that the c-region must be in an extended conformation; since transmembrane segments in integral membrane proteins are generally longer and more hydrophobic than the h-region of signal peptides, these segments may not be able to be properly positioned at the catalytic site. However, this idea was challenged by a recent experiment in which both the lack of transmembrane region of signal peptidases and mutations in the h-region of signal peptides did not affect the correct cleavage site selection. 178 Structures of the mature protein can also affect the cleavage. For example, removal of N-terminal cytoplasmic tail of a type II membrane anchor protein could lead to the cleavage of its transmembrane region; 179 in another example, the transmembrane region near the C terminus can affect the cleavage of signal peptides. 180 Thus, the prediction of signal-anchored proteins is still a difficult problem (see Section 14.5.1). 14.4.2.3 Other Types of Signal Peptidases Type II signal peptidases (signal peptidases II) are found in eubacteria but not in archaea. These peptidases cleave the signal peptides of so-called lipoproteins (lipidmodified proteins) after the lipid modification. They show a clearer substrate specificity than type I peptidases: the lipobox, is typically represented as LA(G/A) | C, where | denotes the cleavage site. 181,182 The cysteine residue is linked by a fatty acid and the protein is anchored at the membrane with this lipid molecule. The leucine at the –3 position may be other large hydrophobic residues. In B. subtilis, signal peptidase II is required for efficient secretion of α-amylase, a nonlipoprotein. 183 Therefore, the substrate specificity of signal peptidase II may not be restricted to lipoproteins. The third type of signal peptidase is PilD (XcpA), which specifically cleaves preproteins related to pilus biogenesis, 184-186 which is related to the so-called type II protein export pathway. 187 In this pathway, the leader sequences are exceptional in that they are basic and short. PilD not only cleaves these leader peptides but also subsequently monomethylates the newly exposed N-terminal phenylalanine.
308 Cell-Penetrating Peptides: Processes and Applications SRP-dependent SRP-independent Tat-dependent SPase II-dependent FIGURE 14.2 Various types of signal peptides. In bacteria, many of SRP-dependent signal peptides are signal anchors of multispanning membrane proteins while most mammalian signal peptides are SRP-dependent but cleavable. In an example of SRP-independent signal peptides, the labels of the tripartite structure are shown. In addition, basic residues (K and R) in the n-region are shown in bold face; hydrophobic h-regions are shown with gray boxes; cleavage sites are shown with vertical lines with the labels of important positions around them. In a Tat-dependent signal peptide, the most important region, including the twin-arginine motif, is boxed. In an SPase II-dependent signal peptide, the lipobox motif around the cleavage site is boxed, too. 14.4.3 DETERMINANTS OF SPECIFICITY As described earlier, prokaryotes and eukaryotes have multiple translocation pathways dependent on signal peptides. Therefore, there must be some specificity determinants within the amino acid sequence of preproteins (Figure 14.2). In addition, signal peptides must be distinguished from other sorting signals within eukaryotic cells. 188 Last, it might be possible that signal peptides could carry the information of the final localization site, i.e., the outer membrane of Gram-negative bacteria. Here, such sequence determinants of signal peptides are discussed. 14.4.3.1 Eubacterial Signal Peptides (uncleavable) 33 ... K I I V S T V V C I G L L L V L V Q L A F P T S F A I R ... n-region h-region c-region M R F P S I F T A V L F A A S S A L A A P ... -3 -1 +1 M K F V K R R I I A L V T I L M L S V T S L F A L Q P S A K A A E H ... M K K R W S I V T L M L I F T L V L S A C G ... If a signal peptide can specify one of the available translocation pathways, it might be also possible that it can specify the final localization site (e.g., the periplasm or the outer membrane of E. coli) of the protein where it resides. In fact, some statistical analyses showed that fine sequence features of signal peptides somehow correlate with the final localization sites. 189,190 Although it is widely believed that signal peptides do not determine final localization, 191 these results may reflect some correlation between localization sites and their targeting pathways.
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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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Interactions of Cell-Penetrating Pe
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Structure Prediction of CPPs and It
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FIGURE 9.7 (Color Figure 9.7 follow
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FIGURE 9.8 The center of the figure
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Biophysical Studies of Cell-Penetra
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Toxicity and Side Effects of Cell-P
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Cell-Penetrating Peptides as Vector
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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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