Stimulated endocytosis in penetratin uptake: Effect of arginine and lysine

Åmand, Helene L.; Fant, Kristina; Nordén, Bengt; Esbjörner, Elin K.

doi:10.1016/j.bbrc.2008.04.039

Cited by 126 publications

(111 citation statements)

References 36 publications

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“…Studies revealed that the levels of internalization with PenArg were 10 times higher than those seen with PenLys, indicating that arginine interacted more strongly with phospholipid membranes than lysine. Å mand et al (39) membrane and degree of cellular internalization, demonstrating conclusively an almost linear correlation between the two factors and verifying the previously unsubstantiated supposition that strength of interaction with the cell membrane is the crucial first consideration in deciphering CPP mechanism of internalization . Self-stimulated macropinocytosis was also shown to be the primary mechanism of membrane translocation for the PenArg CPP.…”

Section: Membrane Destabilizationmentioning

confidence: 56%

“…In a landmark study, cell surface activity and internalization was examined using Penetratin (RQIKI WFQNR RMKWK K-amide), a 16 amino acid peptide derived from the third helix of the Antennapedia homeodomain, PenArg (RQIR IWFQ NRRM RWRR-amide) and PenLys (KQIK IWFQ NKKM KWKK-amide) (39) . Studies revealed that the levels of internalization with PenArg were 10 times higher than those seen with PenLys, indicating that arginine interacted more strongly with phospholipid membranes than lysine.…”

Section: Membrane Destabilizationmentioning

confidence: 99%

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Designer peptide delivery systems for gene therapy

Loughran

McCrudden

McCarthy

2015

European Journal of Nanomedicine

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: Gene therapy has long been hailed as a revolutionary approach for the treatment of genetic diseases. The enthusiasm that greeted the harnessing of viruses for therapeutic DNA delivery has been tempered by concerns over safety. These concerns led to the development of alternative strategies for nucleic acid delivery to cells. One such strategy is the utilization of cationic peptides for the condensation of therapeutic DNA for delivery to its target. However, success of DNA as a therapy relies on its delivery to the nucleus of target cells, a process that is complicated by the many hurdles encountered following systemic administration. Non-viral peptide gene delivery strategies have sought inspiration from viruses in order to retain DNA delivering potency, but limit virulence. This review summarizes the progression of peptide-based DNA delivery systems, from rudimentary beginnings to the recent development of sophisticated multi-functional vectors that comprise distinct motifs with dedicated barrier evasion functions. The most promising peptides that achieve cell membrane permeabilization, endosomal escape and nuclear delivery are discussed.

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Section: Membrane Destabilizationmentioning

confidence: 56%

Section: Membrane Destabilizationmentioning

confidence: 99%

Designer peptide delivery systems for gene therapy

Loughran

McCrudden

McCarthy

2015

European Journal of Nanomedicine

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“…111 For example, the uptake efficiency of an all-Arg analog of penetratin was higher than the wild-type peptide, which contains three Arg molecules and four Lys molecules, whereas an all-Lys analog had lower translocation abilities. 111 Thus, the similarly short 13 CA 31 P distances of Arg10 and Lys13 side chains were at first puzzling. However, these distances were measured in the gel-phase membrane to freeze lipid motions.…”

Section: Different Roles Of Arg and Lys In Membrane Translocationmentioning

confidence: 96%

Structure and dynamics of cationic membrane peptides and proteins: Insights from solid‐state NMR

Hong¹,

Su²

2011

Protein Science

130

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Many membrane peptides and protein domains contain functionally important cationic Arg and Lys residues, whose insertion into the hydrophobic interior of the lipid bilayer encounters significant energy barriers. To understand how these cationic molecules overcome the free energy barrier to insert into the lipid membrane, we have used solid-state NMR spectroscopy to determine the membrane-bound topology of these peptides. A versatile array of solid-state NMR experiments now readily yields the conformation, dynamics, orientation, depth of insertion, and site-specific protein-lipid interactions of these molecules. We summarize key findings of several Arg-rich membrane peptides, including b-sheet antimicrobial peptides, unstructured cell-penetrating peptides, and the voltage-sensing helix of voltage-gated potassium channels. Our results indicate the central role of guanidinium-phosphate and guanidinium-water interactions in dictating the structural topology of these cationic molecules in the lipid membrane, which in turn account for the mechanisms of this functionally diverse class of membrane peptides.

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“…Related, there is strong evidence that lysine to arginine mutations result in improved translocation efficiency. 27 This improvement could be explained by the larger number of HB formed by the mutant arginines, suggesting a penetration mechanisms led by arginines and their direct strong interactions with the membrane.…”

Section: B Penetratin's Orientationmentioning

confidence: 99%

Structure and dynamics of Penetratin’s association and translocation to a lipid bilayer

General

Asciutto

2017

AIP Advances

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Penetratin belongs to the important class of small and positively charged peptides, capable of entering cells. The determination of the optimal peptidic structure for translocation is challenging; results obtained so far are varied and dependent on several factors. In this work, we review the dynamics of association of Penetratin with a modeled dioleoyl-phosphatidylcholine (DOPC) lipid membrane using molecular dynamics simulations with last generation force fields. Penetratin’s structural preferences are determined using a Markov state model. It is observed that the peptide retains a helical form in the membrane associated state, just as in water, with the exception of both termini which lose helicity, facilitating the interaction of terminal residues with the phosphate groups on the membrane’s outer layer. The optimal orientation for insertion is found to be with the peptide’s axis forming a small angle with the interface, and with R1 stretching toward the bilayer. The interaction between arginine side-chains and phosphate groups is found to be greater than the corresponding to lysine, mainly due to a higher number of hydrogen bonds between them. The free energy profile of translocation is qualitatively studied using Umbrella Sampling. It is found that there are different paths of penetration, that greatly differ in size of free energy barrier. The lowest path is compatible with residues R10 to K13 leading the way through the membrane and pulling the rest of the peptide. When the other side is reached, the C-terminus overtakes those residues, and finally breaks out of the membrane. The peptide’s secondary structure during this traversal suffers some changes with respect to the association structure but, overall, conserves its helicity, with both termini in a more disordered state.

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Stimulated endocytosis in penetratin uptake: Effect of arginine and lysine

Cited by 126 publications

References 36 publications

Designer peptide delivery systems for gene therapy

Designer peptide delivery systems for gene therapy

Structure and dynamics of cationic membrane peptides and proteins: Insights from solid‐state NMR

Structure and dynamics of Penetratin’s association and translocation to a lipid bilayer

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