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Signal Peptides 297 1. In the cytosol, the ribosome binds mRNA regardless of whether it codes a secretory protein. 2. The ribosome begins to synthesize the polypeptide according to the bound mRNA. 3. When about 80 amino acid residues protrude from the ribosome, the peptide can interact with the signal recognition particle (SRP). If the polypeptide includes an N-terminal signal peptide, the SRP recognizes it and transiently stops translation of the polypeptide. 4. The SRP–ribosome complex moves to the ER membrane and the SRP binds to the membrane-bound SRP receptor. Then, the translation restarts. 5. The ribosome binds to the translocon channel on the ER membrane. 6. The gate of the translocon opens and the ribosome pushes the elongated polypeptide into the pore of the channel. 7. During or after translation, a signal peptidase cleaves the signal sequence. 8. When the completed protein is released, the complex is dissociated and the channel pore closes. This hypothesis can also explain the assembly process of integral membrane proteins in which signal or signal-like hydrophobic segments start transfer across the membrane while other hydrophobic segments serve as the stop-transfer signal. 6-9 The validity of the signal hypothesis has been verified by many later experiments. Its basic idea also holds for translocation in prokaryotes; furthermore, proteins destined to other compartments such as mitochondria and chloroplasts also have specific sorting signals. Because the signal hypothesis was so beautiful, people believed in a quite simple dogma based on it: although there is no simple consensus sequence pattern between amino acid sequences of signal peptides, they are believed to code a common function. Namely, the signal peptide cotranslationally directs the protein to the SRPdependent pathway in eukaryotes while it post-translationally directs the protein to the Sec system (the protein translocation system dependent on SecA/SecYEG) in prokaryotes. 10 However, recent studies have begun to clarify that the real situation is a little more complex. Thus, the main purpose of this review is to introduce recent developments in the study of protein translocation, including computational and genome-wide studies. 14.2 PROTEIN SECRETION PATHWAYS IN BACTERIA Early studies of protein secretion in bacteria were focused on genetic studies because of the difficulty of construction of in vitro translocation assay. At first, the parallelism between prokaryotic and eukaryotic systems was recognized; namely, that SecB protein and SecYEG channel were analogous to SRP and translocon, respectively, although this translocation process occurs post-translationally in prokaryotes. However, it turned out that there are several other translocation pathways, including the cotranslational SRP-dependent pathway, in bacteria (Figure 14.1). The translocation pathways of archaea are recently described elsewhere. 11,12
298 Cell-Penetrating Peptides: Processes and Applications Signal peptidase FIGURE 14.1 Protein targeting pathways to the cytoplasmic membrane in bacteria. Pathways are roughly classified based on the Sec (SecA/SecYEG) dependence. In E. coli, Sec-dependent pathways are either SecB-dependent or SRP-dependent but another Sec-dependent pathway may exist. For some SRP/SecYEG-dependent proteins, SecA may not be required. The role of YidC is under investigation but it is related to both Sec-dependent and Sec-independent pathways. Signal peptidases also affect the fate of signal peptides. 14.2.1 SECB-DEPENDENT PATHWAY SecB protein plays an important (but not essential) role in translocation of proteins across the cytoplasmic membrane of Gram-negative bacteria. The Sec-system was originally thought to be totally SecB-dependent and the pathway was called “general secretory pathway” (GSP). 13 The current view 14-20 of a SecB-dependent pathway is that a preprotein (i.e., a protein with a signal peptide) protruding from a ribosome is recognized by SecB, which keeps the preprotein in an unfolded state (the translocation-competent state); the SecB–preprotein complex somehow moves to the membrane-bound SecYEG–SecA complex. SecB tightly interacts with SecA and then the preprotein is passed to the SecYEG protein-conducting channel; the preprotein starts translocation and SecB is released. Recent findings related to molecular recognition are further described next. 14.2.1.1 SecB SecA SecYEG Ribosome SecB dependent FtsY SRP dependent Signal peptide Sec-independent Tat dependent YidC YidC Tat As noted, SecB first recognizes a nascent protein. Thus, the central issue of signal recognition could be its substrate specificity, which has been, however, a controversial matter. For one thing, SecB binds to many unfolded proteins in vitro 21 while it shows highly selective binding in vivo. 22 For another thing, there is apparently contradicting evidence on whether SecB is a specific signal-recognition factor or not. 23-25 Most studies seem to support the notion that SecB is a general chaperone
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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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1 CONTENTS 0-8493-1141-1/02/$0.00+$
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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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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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