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Signal Peptides 301 more important structure, the finger-loop structure, was observed. Furthermore, it was found that the proposed signal peptide-binding groove lies alongside the RNA backbone. Thus, it is likely that RNA and protein constitute a signal peptide-binding site. 62 This hypothesis is consistent with an observation that RNA increases the affinity of Ffh for signal peptides. 64 In fact, signal peptides bind the RNA component of SRP. 65 It seems that the 4.5S RNA stabilizes the hydrophobic finger loop, 66 thus catalyzing the assembly of Ffh and the FtsY receptor. 67 Then, SRP binds the ribosome-nascent chain complex (RNC) and targets it to the membrane-bound FtsY. 14.2.2.2 FtsY FtsY, the receptor of bacterial SRP, is homologous to eukaryotic SRα. Its structure is roughly divided into two domains: the NG-domain, which has GTPase and Ffh binding activities, and the N-terminal domain (A-domain in E. coli), which is not well conserved across species but responsible for its membrane targeting. In the eukaryotic system, the signal receptor (SR) is bound by SRβ, an integral membrane protein. Since the homolog of SRβ has not been discovered in bacteria, how FtsY binds the membrane is not known. A crystallographic structure of the E. coli NG domain was determined. 68 Interestingly, the structure of the NG domain of FtsY is similar to the NG domain of Ffh, although its meaning is not well understood. Anyway, in a GTP-dependent manner, RNC is released from the SRP/FtsY complex to the SecYEG complex, 69 although some inner membrane proteins containing long periplasmic loops do not require the Sec-translocase. 70,71 Then, the ribosome restarts the translation, leading to cotranslational translocation of the nascent polypeptide; however, the details of each step are not known. SRP may operate downstream of SR-mediated targeting of ribosomes to the inner membrane in E. coli. 72 SecA is necessary for this pathway, but its role is still under investigation. 73 It has been reported that SecA is not necessary for the targeting but is required for subsequent translocation of multispanning, hydrophobic membrane proteins. 74 14.2.3 TAT-DEPENDENT PATHWAY In this chapter the word “Tat” means not the Tat protein of HIV (as in Chapter 1) but the twin arginine translocation pathway of proteins. Recent studies have clarified that bacteria have another protein translocation pathway independent of the general secretory pathway for a subset of periplasmic proteins. 75,76 The pathway was named Tat protein export pathway because the signal peptides that direct joined proteins to this pathway are similar to usual signal peptides but have a characteristic twinarginine translocation motif (see Section 14.4.3.1); the system was also called Mtt for membrane targeting and transport. 77-80 Although not all bacteria use this translocation system, it is analogous to the ∆pH-dependent pathway across the thylakoid membrane of plant chloroplasts. 81-83 The most intriguing feature of the Tat-dependent pathway (and the ∆pH-dependent pathway) is that it can translocate folded proteins directly. Thus, it makes sense that many of the substrates of this pathway are
302 Cell-Penetrating Peptides: Processes and Applications periplasmic cofactor-binding proteins. Although it seems possible that the pathway proofreads the folding state of its substrates, even malfolded proteins may pass through it. 84 The system also translocates oligomerized proteins; in fact, a protein without the Tat signal can safely translocate the membrane as a complex by a socalled hitchhiker mechanism. 85 Although details of its transport mechanism have not been fully investigated, at least four integral membrane proteins are involved in the translocation system in E. coli: TatA, TatB, TatC, and TatE. 86 TatA, TatB, and TatC are coded in the same tatABCD operon and TatA, TatB, and TatE are similar in sequence. Whether these proteins comprise a channel is not known. The translocation is driven by the proton motive force. Which protein recognizes the signal is also an enigma, but recently DmsD (YnfI) has been proposed as a Tat leader-binding protein. 87 Another study based on two paralogous TatC proteins in Bacillus subtilis, indicated that TatC seems to be a specificity determinant of the pathway. 88 14.2.4 UNKNOWN OR FACTOR-INDEPENDENT PATHWAY 14.2.4.1 Insertion of Procoat Proteins After the entire genome sequences of many bacteria were determined, some possibility still existed of yet-uncharacterized protein translocation pathways. Some excreted (i.e., secreted to the extracellular medium, which means an additional translocation across the outer membrane in Gram-negative bacteria) proteins translocate the inner membrane with a variety of their own transport machinery. 89,90 Although such pathways are out of the scope of this review, it seems noteworthy that SecB is likely to be involved in one of the branches, the ABC-mediated pathway. 91,92 Other proteins even appear to translocate the membrane without the aid of other protein factors. For example, procoat, i.e., precursor of coat, proteins of bacteriophages Pf3 and M13 have been well studied as model systems for Sec-independent protein transport. 93-95 Neither SRP nor SecB is required for these transports. 96 Previously, it had been thought that insertion occurs spontaneously for these proteins, partly because they are rather small and partly because they can be inserted into the membrane of liposomes when electrochemical potential is between both sides of the membrane. 94 However, when the ex<strong>press</strong>ion of YidC was depleted, the translocation of newly synthesized M13 procoat proteins was almost completely inhibited. 97 Thus, YidC not only facilitates Sec-dependent protein translocation but also helps Sec-independent proteins to be inserted into the membrane. 52 A recent study using various procoat mutants showed that substrate proteins can bind to SecA but cannot activate its ATPase activity, in some cases. 98 Another study suggests that YidC is involved in the lateral transfer of transmembrane domains of substrates from the translocase into the lipid bilayer. 99 14.2.4.2 Energetic Aspects Although the in vivo role of spontaneous insertion mechanisms becomes unclear, the interaction of signal peptides with lipids might be of special interest. 41,100 Signal
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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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Toxicity and Side Effects of Cell-P
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Toxicity and Side Effects of Cell-P
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Page 300 and 301: Kinetics of Uptake of Cell-Penetrat
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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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