Membrane-permeable arginine-rich peptides and the translocation mechanisms

Futaki, Shiroh

doi:10.1016/j.addr.2004.10.009

Cited by 385 publications

(331 citation statements)

References 60 publications

Supporting

Mentioning

320

Contrasting

Unclassified

Order By: Relevance

“…By adding arginine-rich sequences (Arg 11 ) to the peptides, RIAD-Arg 11 and scRIAD-Arg 11 (negative control) translocated rapidly and efficiently into the cells (ϳ10 min), 6 consistent with previous reports (51). The selectivity of RIAD for type I PKA was clearly demonstrated in two defined biological systems; RIAD had no effect on type II PKA-regulated AMPA-responsive currents in hippocampal neurons but clearly perturbed type I PKA-mediated inhibition of T cell function by displacing anchored type I PKA from lipid rafts, which reduced Tyr-505 phosphorylation of Lck and up-regulated T cell receptor signaling.…”

Section: Discussionsupporting

confidence: 74%

Delineation of Type I Protein Kinase A-selective Signaling Events Using an RI Anchoring Disruptor

Carlson

Lygren

Berge

et al. 2006

Journal of Biological Chemistry

137

155

View full text Add to dashboard Cite

Control of specificity in cAMP signaling is achieved by A-kinase anchoring proteins (AKAPs), which assemble cAMP effectors such as protein kinase A (PKA) into multiprotein signaling complexes in the cell. AKAPs tether the PKA holoenzymes at subcellular locations to favor the phosphorylation of selected substrates. PKA anchoring is mediated by an amphipathic helix of 14 -18 residues on each AKAP that binds to the R subunit dimer of the PKA holoenzymes. Using a combination of bioinformatics and peptide array screening, we have developed a high affinity-binding peptide called RIAD (RI anchoring disruptor) with >1000-fold selectivity for type I PKA over type II PKA. Cell-soluble RIAD selectively uncouples cAMP-mediated inhibition of T cell function and inhibits progesterone synthesis at the mitochondria in steroid-producing cells. This study suggests that these processes are controlled by the type I PKA holoenzyme and that RIAD can be used as a tool to define anchored type I PKA signaling events.The cAMP signaling pathway synchronizes a variety of physiological responses including cell proliferation and differentiation, microtubule dynamics, reproductive function, modulation of immune responses, and steroidogenesis (1-3). Many of these responses require activation of the cAMP-dependent protein kinase (PKA).3 The dormant PKA holoenzyme is a heterotetramer composed of two catalytic (C) subunits held in an inactive conformation by a regulatory (R) subunit dimer. Upon activation with cAMP, the C subunits are released from their interaction with the R subunit dimer and are free to phosphorylate a plethora of target substrates. Individual cells express a range of PKA isozymes differing in R (RI␣, RI␤, RII␣, RII␤) and C (C␣, C␤, C␥) subunit composition. The type I and type II PKA isozymes, which are classified on the basis of their R subunit dimer, possess slightly different physical and biological properties including a differential sensitivity to cAMP.Spatiotemporal regulation of PKA phosphorylation events is facilitated by A-kinase anchoring proteins (AKAPs). This family of structurally diverse but functionally related proteins act as molecular scaffolds to cluster PKA with specific substrates and signal termination enzymes such as phosphatases (4, 5) and cAMP-specific phosphodiesterases (6 -9). The number of AKAPs has been estimated to more than 75, of which ϳ50 have been identified to date (3, 10). Although the majority of AKAPs described to date bind type II PKA via the RII regulatory subunit, several dual function AKAPs are capable of interacting with both the type I and the type II PKA holoenzyme (11-15). There are also examples of anchoring proteins such as AKAPce (16), PAP7 (17), and merlin (18) that selectively interact with the RI subunit of PKA.The molecular basis for PKA anchoring is the interaction of an amphipathic helical motif of 14 -18 residues on the AKAP with a hydrophobic groove in the N-terminal dimerization domain of the R subunit. High affinity peptides mimicking the amphipathic helix bind to the R...

show abstract

Section: Discussionsupporting

confidence: 74%

Delineation of Type I Protein Kinase A-selective Signaling Events Using an RI Anchoring Disruptor

Carlson

Lygren

Berge

et al. 2006

Journal of Biological Chemistry

137

155

View full text Add to dashboard Cite

show abstract

“…Recent studies have shown that the scorpion toxin maurocalcine crosses the plasma membrane, reaches its target channel located in the endoplasmic reticulum, and consequently causes calcium release from intracellular stores (54). It has been suggested that maurocalcine behaves similarly to the well known cell-penetrating peptides (55), such as the human immunodeficiency virus Tat peptide (56), although recent efforts to understand the translocation mechanism of cell-penetrating peptides have revealed greater complexity involving multiple pathways (57)(58)(59). Interestingly, similar to CTX A3, polypeptides with cell penetrating capability usually are amphiphilic and contain positively charged clusters that are capable of targeting the cell surface by binding to heparan sulfate in the extracellular matrix and/or anionic lipids in the membrane bilayer (60 -62).…”

Section: Discussionmentioning

confidence: 99%

Glycosphingolipid-facilitated Membrane Insertion and Internalization of Cobra Cardiotoxin

Wang

Liu

Lee

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cobra cardiotoxins, a family of basic polypeptides having lipidand heparin-binding capacities similar to the cell-penetrating peptides, induce severe tissue necrosis and systolic heart arrest in snakebite victims. Whereas cardiotoxins are specifically retained on the cell surface via heparan sulfate-mediated processes, their lipid binding ability appears to be responsible, at least in part, for cardiotoxin-induced membrane leakage and cell death. Although the exact role of lipids involved in toxin-mediated cytotoxicity remains largely unknown, monoclonal anti-sulfatide antibody O4 has recently been shown to inhibit the action of CTX A3, the major cardiotoxin from Taiwan cobra venom, on cardiomyocytes by preventing cardiotoxin-induced membrane leakage and CTX A3 internalization into mitochondria. Here, we show that anti-sulfatide acts by blocking the binding of CTX A3 to the sulfatides in the plasma membrane to prevent sulfatide-dependent CTX A3 membrane pore formation and internalization. We also describe the crystal structure of a CTX A3-sulfatide complex in a membrane-like environment at 2.3 Å resolution. The unexpected orientation of the sulfatide fatty chains in the structure allows prediction of the mode of toxin insertion into the plasma membrane. CTX A3 recognizes both the headgroup and the ceramide interfacial region of sulfatide to induce a lipid conformational change that may play a key role in CTX A3 oligomerization and cellular internalization. This proposed lipid-mediated toxin translocation mechanism may also shed light on the cellular uptake mechanism of the amphiphilic cell-penetrating peptides known to involve multiple internalization pathways.Glycosphingolipids in eukaryotic cells have important biological functions in membrane trafficking and cell signaling (1, 2). The number of disease-related proteins found to interact specifically with glycosphingolipids is also increasing (3-5). For instance, recent studies have shown that natural killer cells can be activated by glycosylceramides from the cell surface of Gram-negative bacteria that do not contain lipopolysaccharide (6, 7). There is also evidence indicating that, in response to tumor necrosis factor-␣, trafficking of ganglioside GD3 from the plasma membrane to mitochondria can trigger several cell death signaling responses (3,8,9). Although the molecular mechanisms accounting for the observed glycosphingolipid transport and glycolipidtriggered cell responses remain elusive, recent progress in determining the three-dimensional structure of protein⅐glycosphingolipid complexes has shed some light on the process (10 -13). These glycosphingolipid-binding proteins function by either extracting lipids from the membrane and forming a water-soluble protein⅐lipid complex, as in the cases of glycosphingolipid transfer protein, saposin B, and lipid-presenting CD1a (10 -12), or by localizing to a glycosphingolipid domain of the plasma membrane and eventually being internalized via the endocytic pathway, as seen for cholera and Shiga toxins (13,14). Aft...

show abstract

“…As a matter of fact, there has been a profusion of publications highlighting one or another entry route, sometimes with some obvious discrepancies. CPP-mediated transport has been shown, so far, to mainly follow a cellular endocytosis-mediated uptake [36][37][38].…”

Section: Cpps and Cell Entrymentioning

confidence: 99%

Cell-penetrating and cell-targeting peptides in drug delivery

Vivès

Schmidt

Pèlegrin

2008

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

310

272

View full text Add to dashboard Cite

During the last decade, the potential of peptides for drug delivery into cells has been highlighted by the discovery of several cell-penetrating peptides (CPPs). CPPs are very efficient in delivering various molecules into cells. However, except in some specific cases, their lack of cell specificity remains the major drawback for their clinical development. At the same time, various peptides with specific binding activity for a given cell line (cell-targeting peptides) have also been reported in the literature. One of the goals of the next years will be to optimize the tissue and cell delivery of therapeutic molecules by means of peptides which combine both targeting and internalization advantages. In this review, we describe the main strategies that are currently in use or likely to be employed in the near future to associate both targeting and delivery properties.

show abstract

Membrane-permeable arginine-rich peptides and the translocation mechanisms

Cited by 385 publications

References 60 publications

Delineation of Type I Protein Kinase A-selective Signaling Events Using an RI Anchoring Disruptor

Delineation of Type I Protein Kinase A-selective Signaling Events Using an RI Anchoring Disruptor

Glycosphingolipid-facilitated Membrane Insertion and Internalization of Cobra Cardiotoxin

Cell-penetrating and cell-targeting peptides in drug delivery

Contact Info

Product

Resources

About