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Signal Peptides 303 peptides are thought to be inserted into the membrane in a helix–beak–helix conformation consistent with the classical helical hairpin hypothesis. 101,102 At this process, the length of the hydrophobic region of signal peptides seems to play an important role. 103 The interaction between their positively charged N termini and the anionic phospholipids is also important for determining the orientation of insertion. 104 Namely, positively charged residues are not favored for transportation across the membrane; this seems to be the major determinant of the topology of membrane proteins (the positive-inside rule). 105,106 In another study, the proton motive force (pmf), which renders the cytoplasm basic and the periplasm acidic, was shown to inhibit membrane translocation of positively charged residues within membrane proteins. 107,108 However, the determinants of the positive-inside rule seem still to be controversial. 109 Negatively charged residues are also likely to be involved in the translocation. 110 When there are no charged amino acids around the signal peptide, anionic lipids stimulate its translocation in a direction opposite to the positive-inside rule, possibly because of its helix dipole moment. 111 Factors that influence the efficiency and specificity of signal peptides will be discussed in Section 14.4.3.1. 14.3 PROTEIN SECRETION PATHWAYS IN EUKARYOTES In eukaryotes, it is quite established that proteins transported through the secretory pathway have a signal peptide, including an uncleavable signal anchor, on their N terminus and are first transported to the ER, although there are some exceptions. Unlike the bacterial system, most of the signal peptides are cotranslationally recognized by SRP, although some proteins are transported through the post-translational pathway, especially in yeast. In addition, chloroplasts (and mitochondria) seem to have their own transport system directed by signal peptide-related signals. Here, eukaryote-specific topics are briefly summarized. 4,5,112-117 Translocation via signal peptide-like signals within mitochondria and chloroplasts is reviewed elsewhere. 52,118-120 14.3.1 COTRANSLATIONAL PATHWAY 14.3.1.1 Targeting to the ER Mammalian SRP consists of 6 proteins and 1 RNA (7S RNA). All known SRPrelated sequences are maintained in a public database (SRPDB). 121 SRP54, a homolog of bacterial Ffh, recognizes signal peptides and has GTPase activity. Although still controversial, the nascent polypeptide-associated complex (NAC), which is an abundant cytosolic heterodimer, has been proposed to first contact the nascent polypeptide chain emerging from the ribosome and to strengthen the specificity of SRP for binding signal peptides and for targeting to the ER. 122-124 Although ribosome–nascent chain (RNC) complexes can be targeted and bind to the ER membrane without the aid of SRP, the binding of RNC complexes with SRP gives it a competitive advantage. 125
304 Cell-Penetrating Peptides: Processes and Applications SRP binds to the SRP receptor (SR) on the ER. Unlike bacteria, SR is a heterodimer consisting of SRα and SRβ. SRα, a peripheral subunit, is homologous to bacterial FtsY while SRβ, an integral membrane, does not have its bacterial counterpart. Both subunits of SR have a GTPase domain. With the binding of SRP and SR, the GTPase activities of SRP54 and SRα increase. Then, the RNC complex is passed to the translocon and the SRP is dissociated. 126 SRβ coordinates signal peptide release from SRP. 127 14.3.1.2 Translocon Complex In mammals and yeasts, the translocon is thought to consist basically of three subunits, Sec61α (Sec61p), Sec61β (Sbh1p), and Sec61γ (Sss1p). 116 Sec61α and Sec61γ are similar to bacterial SecY and SecE, respectively, while Sec61β, a nonessential protein, is not similar to SecG. For translocation of at least some mammalian preproteins, the TRAM (translocating chain-associated membrane) protein plays an important role. 128 TRAM is an integral membrane protein and seems to recognize signal peptides. 129 However, the exact role of TRAM is still unclear and no homologs of TRAM exist in yeast. The translocon is thought to form an aqueous gated pore. 130 Although there may be other receptors for the RNC, Sec61α directly binds to it. 131 Moreover, the Sec61-complex seems to recognize the signal sequence specifically, which is crucial in regulating translocation efficiency. 132-135 Thus, signal peptides are recognized at least twice by different proteins. The translocation of polytopic membrane proteins is thought to be basically the same as that of secreted proteins. 136 Due to the complete sequencing of the yeast genome, a homolog of Sec61p, Ssh1p, was discovered. Although SSH1 is not an essential gene, recent studies show that Ssh1p acts with Sss1p and Sbh2p (a close homolog of Sbh1p) as a second, functionally distinct translocon. 137,138 14.3.2 POST-TRANSLATIONAL PATHWAY In both yeast and mammalian cells, relatively few proteins translocate the ER membrane post-translationally. 139 In yeast, its molecular mechanism is rather known. Unlike the cotranslational pathway, SRP, SR, and TRAM are not involved in this pathway. Instead, several additional proteins are required. 14.3.2.1 Additional Membrane Proteins As with the cotranslational pathway, translocation occurs through the Sec61 complex. In addition, several membrane proteins, including three integral (Sec62p, Sec63p, and Sec71p) and one peripheral (Sec72p), are required. These proteins form a stable heterotetrameric complex which also interacts with the Sec61 translocon. Homologs of Sec62p and Sec63p also exist in mammals. 140 According to a current model, a preprotein first binds to the Sec62p–Sec71p–Sec72p (and possibly Sec63p) complex, which is signal peptide-dependent but ATP-independent. 141 Then, the preprotein is possibly transferred to the Sec61 complex in an ATP-dependent manner (see below). Sec63p is partly similar to bacterial DnaJ protein, which stimulates the ATPase activity of DnaK, a bacterial hsc70 (heat shock cognate 70) molecular
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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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TABLE 16.1 Examples of Transport of
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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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