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3 pages, 168 KiB

Open AccessEditorial

Special Issue: Advances of Peptide Engineering

by Kenji Usui and Kin-ya Tomizaki

Processes 2021, 9(7), 1096; https://doi.org/10.3390/pr9071096 - 24 Jun 2021

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Abstract

Peptides have been gaining increasing attention for their applications in various fields, such as medical, biotechnological, and nanotechnological fields [...] Full article

(This article belongs to the Special Issue Advances of Peptide Engineering)

Research

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9 pages, 1394 KiB

Open AccessArticle

Discovery of Cell Aggregate-Inducing Peptides

by Yudai Futaki, Ikumi Amimoto, Megumi Tanaka, Tomoki Ito and Yoshiaki Hirano

Processes 2021, 9(3), 538; https://doi.org/10.3390/pr9030538 - 18 Mar 2021

Cited by 3 | Viewed by 2059

Abstract

Most cells within the human body interact with neighboring cells and extracellular matrix (ECM) components to establish a unique 3D organization. These cell–cell and cell–ECM interactions form a complex communication network of biochemical and mechanical signals critical for normal cell physiology. The behavior [...] Read more.

Most cells within the human body interact with neighboring cells and extracellular matrix (ECM) components to establish a unique 3D organization. These cell–cell and cell–ECM interactions form a complex communication network of biochemical and mechanical signals critical for normal cell physiology. The behavior of cells in a 3D environment is fundamentally different from that of cells in monolayer culture. Aggregation can affect cell–cell interactions, being more representative of the normal tissue microenvironment. Therefore, 3D cell culture technologies have been developed. The general method for cell aggregate is a physical method; it is difficult to control the size and number of cell aggregates. In any case, no chemical method has been discovered yet, so a new method to solve these problems is needed. In this paper, we describe the induction of a cell aggregate of the newly discovered (Lys-Pro)₁₂(KP24) peptide. Since it was revealed that KP24 had cell aggregate-inducing activity, its derivatives were molecularly designed to clarify the importance of the KP24 sequence. We report that cell aggregations were induced by KP24 to form aggregates of fibroblast cells. We evaluated KP24 derivative periodic peptides such as (Lys-Pro-Pro)₈(KPP24) and (Lys-Lys-Pro)₈(KKP24). The relationship between the structure of the peptide chain and the activity induced by the cell aggregations was investigated from the viewpoint of basic research and the biomedical engineering field. Full article

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11 pages, 9125 KiB

Open AccessArticle

Extraction of Type I Collagen from Tilapia Scales Using Acetic Acid and Ultrafine Bubbles

by Junko Kuwahara

Processes 2021, 9(2), 288; https://doi.org/10.3390/pr9020288 - 02 Feb 2021

Cited by 15 | Viewed by 8235

Abstract

Type I collagen is commonly used in medical materials and cosmetics. While it can be extracted from the skin and bones of mammals, marine collagen has attracted attention recently, since the use of mammalian collagen could result in zoonosis, and products containing mammalian [...] Read more.

Type I collagen is commonly used in medical materials and cosmetics. While it can be extracted from the skin and bones of mammals, marine collagen has attracted attention recently, since the use of mammalian collagen could result in zoonosis, and products containing mammalian collagen are avoided due to some religious beliefs. Chemical extractions using strong acids and alkalis, thermal extractions, and other nonconventional methods have been used for collagen extraction. However, there are few reports on environmentally friendly methods. Although heat extractions provide higher yields of collagen, they often cause collagen denaturation. Therefore, dilute acetic acid and ultrafine bubbles of oxygen, carbon dioxide, and ozone were used to extract type I collagen from tilapia scales. The extraction performance of the different conditions employed was qualitatively analyzed by SDS-PAGE electrophoresis, and the collagen concentration was quantified using circular dichroism spectroscopy by monitoring the peak intensity at 221 nm, which is specific to the triple helix of type I collagen. Collagen was extracted from tilapia scales with a yield of 1.58% by the aeration of ultrafine bubbles of carbon dioxide gas in a 0.1 M acetic acid solution for 5 h. Full article

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8 pages, 1313 KiB

Open AccessFeature PaperArticle

The Effect of a Peptide Substrate Containing an Unnatural Branched Amino Acid on Chymotrypsin Activity

by Yuuki Yamawaki, Tomoki Yufu and Tamaki Kato

Processes 2021, 9(2), 242; https://doi.org/10.3390/pr9020242 - 28 Jan 2021

Cited by 9 | Viewed by 2400

Abstract

7-Amino-4-methylcoumarin (AMC) is a low molecular weight fluorescent probe that can be attached to a peptide to enable the detection of specific proteases, such as chymotrypsin, expressed in certain diseases. Because this detection depends on the specificity of the protease toward the peptidyl [...] Read more.

7-Amino-4-methylcoumarin (AMC) is a low molecular weight fluorescent probe that can be attached to a peptide to enable the detection of specific proteases, such as chymotrypsin, expressed in certain diseases. Because this detection depends on the specificity of the protease toward the peptidyl AMC, the development of specific substrates is required. To investigate the specificity of chymotrypsin, peptidyl AMC compounds incorporating four different amino acid residues were prepared by liquid-phase synthesis. Two unnatural amino acids, 2-amino-4-ethylhexanoic acid (AEH) and cyclohexylalanine (Cha), were used to investigate the substrate specificity as these amino acids have structures different from natural amino acids. AEH was synthesized using diethyl acetamidemalonate as a starting material. The substrate containing Cha had high hydrophobicity and showed a high reaction velocity with chymotrypsin. Although the AEH substrate with a branched side chain had high hydrophobicity, it showed a low reaction velocity. The substrate containing the aromatic amino acid phenylalanine was less hydrophobic than the Cha and AEH substrates, but chymotrypsin showed the highest specificity for this compound. These results demonstrated that the substrate specificity of chymotrypsin is not only affected by the hydrophobicity and aromaticity, but also by the structural expanse of amino acid residues in the substrate. Full article

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11 pages, 3405 KiB

Open AccessArticle

Improvement of Water Solubility of Mercaptoundecahydrododecaborate (BSH)-Peptides by Conjugating with Ethylene Glycol Linker and Interaction with Cyclodextrin

by Mizuki Kitamatsu, Ayaka Nakamura-Tachibana, Yoshimichi Ishikawa and Hiroyuki Michiue

Processes 2021, 9(1), 167; https://doi.org/10.3390/pr9010167 - 18 Jan 2021

Cited by 7 | Viewed by 2577

Abstract

We previously developed a conjugate consisting of ¹⁰B cluster BSH and tri-arginine peptide (BSH-3R). This could potentially be used as a boron agent for boron neutron capture therapy; however, it possesses poor water solubility and thus needs to be improved for use [...] Read more.

We previously developed a conjugate consisting of ¹⁰B cluster BSH and tri-arginine peptide (BSH-3R). This could potentially be used as a boron agent for boron neutron capture therapy; however, it possesses poor water solubility and thus needs to be improved for use as medicine. In this study, we devised several means of improving the water solubility of BSH-3R. As one of them, we used cyclodextrin (CD), which was expected to improve the water solubility resulting from interaction of the BSH-3R with CD. We evaluated the solubility of BSH-3R in aqueous CD solution by using reverse-phase high-performance liquid chromatography. As we expected, the solubility of BSH-3R was increased in a manner dependent on the addition of β-CD and γ-CD in aqueous solution. Furthermore, we synthesized BSH conjugated to oligoarginine having various chain lengths (BSH-nR) and BSH-3R with ethylene glycol linkers introduced between BSH and 3R (BSH-nEg-3R). The water solubility of these BSH peptides was also evaluated and the results showed that the introduction of nEg to BSH-3R markedly improved the water solubility. Furthermore, we found that the water solubility of these peptides can be further improved by also applying CD. Full article

(This article belongs to the Special Issue Advances of Peptide Engineering)

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8 pages, 3856 KiB

Open AccessFeature PaperArticle

Development of Circularly Polarized Luminescence (CPL) Peptides Containing Pyrenylalanines and 2-Aminoisobutyric Acid

by Yuki Mimura, Yuki Motomura, Mizuki Kitamatsu and Yoshitane Imai

Processes 2020, 8(12), 1550; https://doi.org/10.3390/pr8121550 - 27 Nov 2020

Cited by 3 | Viewed by 2176

Abstract

Chiral organic and organometallic luminophores that possess circularly polarized luminescence (CPL) properties in the near-ultraviolet to near-infrared region have several useful applications. However, the CPL properties are subject to inherent factors of the compounds; to date, studies on the CPL properties influenced by [...] Read more.

Chiral organic and organometallic luminophores that possess circularly polarized luminescence (CPL) properties in the near-ultraviolet to near-infrared region have several useful applications. However, the CPL properties are subject to inherent factors of the compounds; to date, studies on the CPL properties influenced by amino acids and peptides are scarce. Consequently, we developed peptide-pyrene organic luminophores exhibiting various CPL properties. It is conceivable that the peptide-pyrene organic luminophores can be obtained as aggregates when dissolved in a solution. It is also possible that the formation of aggregates makes it difficult to accurately examine the CPL of the peptide in the solution. This study showed that the introduction of sterically hindered 2-aminoisobutyric acid (Aib) units into the peptide backbone inhibits aggregate formation. The resulting luminophores exhibit CPL properties owing to the presence of pyrene units. The results of this study can form a basis for the design of future materials that use peptide-pyrene organic luminophores. Full article

(This article belongs to the Special Issue Advances of Peptide Engineering)

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11 pages, 1967 KiB

Open AccessFeature PaperArticle

Design and Construction of pH-Selective Self-Lytic Liposome System

by Ayumi Kashiwada, Kana Namiki and Haruka Mori

Processes 2020, 8(12), 1526; https://doi.org/10.3390/pr8121526 - 24 Nov 2020

Cited by 3 | Viewed by 2204

Abstract

Liposomes are well-investigated drug or gene delivery vehicles for chemotherapy, used by taking advantage of their biocompatibility and biodegradability. A central question on the construction of intracellular liposomal delivery systems is to entrap the liposomes of interest in the highly acidic and proteolytic [...] Read more.

Liposomes are well-investigated drug or gene delivery vehicles for chemotherapy, used by taking advantage of their biocompatibility and biodegradability. A central question on the construction of intracellular liposomal delivery systems is to entrap the liposomes of interest in the highly acidic and proteolytic endosomal environment. In the other words, it is essential that the liposomes release a therapeutic drug into the cytosol before they are degraded in the endosome. As a strategy to enhance the endosome escape, the self-lytic liposomes with acidic pH-selective membrane active polypeptide are considered highly effective. Here, an acidic pH-selective membrane-lytic polypeptide (LPE) and its retro isomer (rLPE) were designed, and then their membrane-lytic activities against EggPC liposomes were determined. It was noticed that the rLPE polypeptide showed an increase in activity compared with the LPE polypeptide. Furthermore, the rLPE polypeptide was conjugated to liposomes via a flexible Gly-Gly-Gly-Gly linker to facilitate the pH-selective content release. The rLPE anchoring liposomes exhibited distinctly different contents release behavior at physiological and endosomal pHs, namely typical contents release from liposomes was positively observed at acidic pH range. The overarching goal of this paper is to develop efficient pH-selective therapeutic delivery systems by using our findings. Full article

(This article belongs to the Special Issue Advances of Peptide Engineering)

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12 pages, 3283 KiB

Open AccessFeature PaperArticle

Horseradish Peroxidase-Decorated Artificial Viral Capsid Constructed from β-Annulus Peptide via Interaction between His-Tag and Ni-NTA

by Kazunori Matsuura, Yuriko Shiomi, Toshihumi Mizuta and Hiroshi Inaba

Processes 2020, 8(11), 1455; https://doi.org/10.3390/pr8111455 - 13 Nov 2020

Cited by 7 | Viewed by 3035

Abstract

Artificial construction of spherical protein assemblies has attracted considerable attention due to its potential use in nanocontainers, nanocarriers, and nanoreactors. In this work, we demonstrate a novel strategy to construct peptide nanocapsules (artificial viral capsids) decorated with enzymes via interactions between His-tag and [...] Read more.

Artificial construction of spherical protein assemblies has attracted considerable attention due to its potential use in nanocontainers, nanocarriers, and nanoreactors. In this work, we demonstrate a novel strategy to construct peptide nanocapsules (artificial viral capsids) decorated with enzymes via interactions between His-tag and Ni-NTA. A β-annulus peptide derived from the tomato bushy stunt virus was modified with Ni-NTA at the C-terminus, which is directed toward the exterior surface of the artificial viral capsid. The β-annulus peptide bearing Ni-NTA at the C-terminus self-assembled into capsids of about 50 nm in diameter. The Ni-NTA-displayed capsids were complexed with recombinant horseradish peroxidase (HRP) with a C-terminal His-tag which was expressed in Escherichia coli. The β-annulus peptide-HRP complex formed spherical assemblies whose sizes were 30–90 nm, with the ζ-potential revealing that the HRP was decorated on the outer surface of the capsid. Full article

(This article belongs to the Special Issue Advances of Peptide Engineering)

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12 pages, 2293 KiB

Open AccessFeature PaperArticle

Tandem-Homodimer of a β-Sheet-Forming Short Peptide Inhibits Random-to-β Structural Transition of Its Original Monomer

by Kin-ya Tomizaki, Tomomi Iori, Hideyasu Fukushima, Yasuhiro Nakabayashi, Yoshiki Matsumoto and Takahito Imai

Processes 2020, 8(11), 1421; https://doi.org/10.3390/pr8111421 - 08 Nov 2020

Cited by 2 | Viewed by 1786

Abstract

There is an increasing interest in designing fibrillogenesis modulators for treating amyloid β (Aβ)-peptide-associated diseases. The use of Aβ fragment peptides and their derivatives, as well as nonpeptidyl natural products, is one promising approach to prevent Aβ fibrillation. In this study, we demonstrate [...] Read more.

There is an increasing interest in designing fibrillogenesis modulators for treating amyloid β (Aβ)-peptide-associated diseases. The use of Aβ fragment peptides and their derivatives, as well as nonpeptidyl natural products, is one promising approach to prevent Aβ fibrillation. In this study, we demonstrate that tandem-homodimers (TDs) of a β-sheet-forming short peptide in which the amino acid sequence is duplicated in series and joined via an amino alkanoic acid linker of different chain lengths, preventing the random-to-β structural transition of the original monomer. Ape5-TD, containing 5-amino pentanoate, most potently prevented this transition for at least five days by generating disordered aggregates with reduced tryptic stability. The linkers in the TDs generated this inhibitory activity, probably due to their bent conformations and hydrophobicity, appropriate for accommodating and twisting the monomers, resulting in irregular arrangements of the peptides. The present study could allow the design of a new class of protein/peptide fibrillogenesis modulators. Full article

(This article belongs to the Special Issue Advances of Peptide Engineering)

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10 pages, 1515 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Synthesis of Peptide-Immobilized Magnetic Beads, and Peptide Reactivity Assay for Assessing Skin Sensitization Utilizing Chromophore

by Hiroshi Miyazaki, Hikaru Takaishi, Hidefumi Ikeda, Hideto Ariumi, Yoshio Hamada, Kunihiko Yamashita and Kenji Usui

Processes 2020, 8(10), 1257; https://doi.org/10.3390/pr8101257 - 07 Oct 2020

Cited by 2 | Viewed by 3354

Abstract

DPRA (direct peptide reactivity assay) and ADRA (amino acid derivative reactivity assay), which are based on the biological events of skin sensitization, were developed as alternatives to the controversial animal experiments. These assays are described in the OECD (Organization for Economic Co-operation and [...] Read more.

DPRA (direct peptide reactivity assay) and ADRA (amino acid derivative reactivity assay), which are based on the biological events of skin sensitization, were developed as alternatives to the controversial animal experiments. These assays are described in the OECD (Organization for Economic Co-operation and Development) guideline, Test No. 442C. Although these assays have been endorsed by the industries and internationally accepted as promising and effective tests for in vitro skin sensitization, they suffer from several drawbacks, such as incompatibility with hydrophobic chemicals and complicated sample processing. Here, we demonstrated a chromophore-based solid phase peptide reaction assay in vitro using peptides immobilized on magnetic beads (C-SPRA-MB). We successfully synthesized lysine (Lys) and cysteine (Cys) immobilized on magnetic microbeads. However, Cys immobilized magnetic microbeads showed gradual decomposition of the magnetic beads due to SH oxidation. Using Lys immobilized magnetic microbeads, we demonstrated the capacity of C-SPRA-MB to predict skin sensitization by measuring free amino groups of the Lys after reaction with test chemicals. First, the free amines on the microbeads were reacted with bromophenol blue (BB). Then, by treatment with a saturated solution of Lys, the bound BBs were released and quantified. C-SPRA-MB provides high-throughput and accurate assays for assessments of chemicals, including with low-potency as skin sensitizers and poor water solubility. C-SPRA-MB may be useful for effective prediction of their skin sensitization potential in the process of compound screening, especially in the case of misclassified by DPRA and ADRA. Thus, C-SPRA-MB can be applied to assessing the sensitization potential of medical, pharmaceutical, cosmetics, and industrial compounds. Full article

(This article belongs to the Special Issue Advances of Peptide Engineering)

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9 pages, 2320 KiB

Open AccessFeature PaperArticle

Preparation of Biocomposite Soft Nanoparticles Composed of Poly(Propylene Oxide) and the Polymer-Binding Peptides

by Toshiki Sawada, Hiroki Fukuta and Takeshi Serizawa

Processes 2020, 8(7), 859; https://doi.org/10.3390/pr8070859 - 17 Jul 2020

Cited by 1 | Viewed by 2627

Abstract

The molecular recognition capability of naturally occurring biomolecules is generally expressed against biomolecules in the biological milieu. Recently, it was demonstrated that the specific interactions of biomolecules such as short peptides were applicable to artificial materials. We have developed peptides with specific affinities [...] Read more.

The molecular recognition capability of naturally occurring biomolecules is generally expressed against biomolecules in the biological milieu. Recently, it was demonstrated that the specific interactions of biomolecules such as short peptides were applicable to artificial materials. We have developed peptides with specific affinities for synthetic polymers toward functional biocomposite polymeric materials. In this study, we demonstrated the preparation of biocomposite nanoparticles composed of poly(propylene oxide) (PPO) and PPO-binding peptides. A simple injection of a concentrated PPO solution dissolved in an organic solvent into the peptide solution under sonication resulted in the formation of nanospherical structures. Morphological observation indicated characteristic softness and high applicability as a molecular carrier of the biocomposite nanoparticles. Structural characterization of PPO and the PPO-binding peptide revealed the structural conformability of these molecules to interact specifically with each other. Our findings expand the potential applicability of polymer-binding peptides for the future construction of biomedical materials composed of peptides and various polymers. Full article

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8 pages, 1140 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Novel Purification Process for Amyloid Beta Peptide(1-40)

by Kenji Usui, Shin-ichiro Yokota, Kazuya Iwata and Yoshio Hamada

Processes 2020, 8(4), 464; https://doi.org/10.3390/pr8040464 - 15 Apr 2020

Cited by 3 | Viewed by 4149

Abstract

Amyloid beta peptide (Aβ)-related studies require an adequate supply of purified Aβ peptide. However, Aβ peptides are “difficult sequences” to synthesize chemically, and low yields are common due to aggregation during purification. Here, we demonstrate an easier synthesis, deprotection, reduction, cleavage, and purification [...] Read more.

Amyloid beta peptide (Aβ)-related studies require an adequate supply of purified Aβ peptide. However, Aβ peptides are “difficult sequences” to synthesize chemically, and low yields are common due to aggregation during purification. Here, we demonstrate an easier synthesis, deprotection, reduction, cleavage, and purification process for Aβ(1-40) using standard 9-fluorenylmethyloxycarbonyl (Fmoc)-protected amino acids and solid-phase peptide synthesis (SPPS) resin [HMBA (4-hydroxymethyl benzamide) resin] that provides higher yields of Aβ(1-40) than previous standard protocols. Furthermore, purification requires a similar amount of time as conventional purification processes, although the peptide must be cleaved from the resin immediately prior to purification. The method described herein is not limited to the production of Aβ(1-40), and can be used to synthesize other easily-oxidized and aggregating sequences. Our proposed methodology will contribute to various fields using “difficult sequence” peptides, such as pharmaceutical and materials science, as well as research for the diagnosis and treatment of protein/peptide misfolding diseases. Full article

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Review

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14 pages, 8492 KiB

Open AccessReview

Exploration of Active Site-Directed Plasmin Inhibitors: Beyond Tranexamic Acid

by Yuko Tsuda, Koushi Hidaka, Keiko Hojo and Yoshio Okada

Processes 2021, 9(2), 329; https://doi.org/10.3390/pr9020329 - 11 Feb 2021

Cited by 3 | Viewed by 2329

Abstract

Plasmin (Plm), a trypsin-like serine protease, is responsible for fibrinolysis pathway and pathologic events, such as angiogenesis, tumor invasion, and metastasis, and alters the expression of cytokines. A growing body of data indicates that a Plm inhibitor is a potential candidate as an [...] Read more.

Plasmin (Plm), a trypsin-like serine protease, is responsible for fibrinolysis pathway and pathologic events, such as angiogenesis, tumor invasion, and metastasis, and alters the expression of cytokines. A growing body of data indicates that a Plm inhibitor is a potential candidate as an anti-inflammatory and anti-cancer agent. A class of active site-directed plasmin inhibitors containing tranexamic acid residue has been designed. As evidenced by docking studies, the inhibitor binds to the active site not to the lysine binding site (LBS) in plasmin, thus preventing plasmin from digesting the substrate. Further optimization of the series, concerning both activity and selectivity, led to the second generation of inhibitors. This review focuses on the Plm inhibitory activity-structure relationship of Plm inhibitors with the goal of realizing their design and clinical application. Full article

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17 pages, 5028 KiB

Open AccessReview

Biofunctional Peptide-Modified Extracellular Vesicles Enable Effective Intracellular Delivery via the Induction of Macropinocytosis

by Ikuhiko Nakase

Processes 2021, 9(2), 224; https://doi.org/10.3390/pr9020224 - 25 Jan 2021

Cited by 19 | Viewed by 4832

Abstract

We previously reported that macropinocytosis (accompanied by actin reorganization, ruffling of the plasma membrane, and engulfment of large volumes of extracellular fluid) is an important process for the cellular uptake of extracellular vesicles, exosomes. Accordingly, we developed techniques to induce macropinocytosis by the [...] Read more.

We previously reported that macropinocytosis (accompanied by actin reorganization, ruffling of the plasma membrane, and engulfment of large volumes of extracellular fluid) is an important process for the cellular uptake of extracellular vesicles, exosomes. Accordingly, we developed techniques to induce macropinocytosis by the modification of biofunctional peptides on exosomal membranes, thereby enhancing their cellular uptake. Arginine-rich cell-penetrating peptides have been shown to induce macropinocytosis via proteoglycans; accordingly, we developed peptide-modified exosomes that could actively induce macropinocytotic uptake by cells. In addition, the activation of EGFR induces macropinocytosis; based on this knowledge, we developed artificial leucine-zipper peptide (K4)-modified exosomes. These exosomes can recognize E3 sequence-fused EGFR (E3-EGFR), leading to the clustering and activation of E3-EGFR by coiled-coil formation (E3/K4), which induces cellular exosome uptake by macropinocytosis. In addition, modification of pH-sensitive fusogenic peptides (e.g., GALA) also enhances the cytosolic release of exosomal contents. These experimental techniques and findings using biofunctional peptides have contributed to the development of exosome-based intracellular delivery systems. Full article

(This article belongs to the Special Issue Advances of Peptide Engineering)

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11 pages, 1039 KiB

Open AccessFeature PaperReview

Methods for Identification of Substrates/Inhibitors of FCP/SCP Type Protein Ser/Thr Phosphatases

by Masataka Mizunuma, Atsushi Kaneko, Shunta Imai, Kazuhiro Furukawa and Yoshiro Chuman

Processes 2020, 8(12), 1598; https://doi.org/10.3390/pr8121598 - 04 Dec 2020

Cited by 2 | Viewed by 2635

Abstract

Protein phosphorylation is the most widespread type of post-translational modification and is properly controlled by protein kinases and phosphatases. Regarding the phosphorylation of serine (Ser) and threonine (Thr) residues, relatively few protein Ser/Thr phosphatases control the specific dephosphorylation of numerous substrates, in contrast [...] Read more.

Protein phosphorylation is the most widespread type of post-translational modification and is properly controlled by protein kinases and phosphatases. Regarding the phosphorylation of serine (Ser) and threonine (Thr) residues, relatively few protein Ser/Thr phosphatases control the specific dephosphorylation of numerous substrates, in contrast with Ser/Thr kinases. Recently, protein Ser/Thr phosphatases were reported to have rigid substrate recognition and exert various biological functions. Therefore, identification of targeted proteins by individual protein Ser/Thr phosphatases is crucial to clarify their own biological functions. However, to date, information on the development of methods for identification of the substrates of protein Ser/Thr phosphatases remains scarce. In turn, substrate-trapping mutants are powerful tools to search the individual substrates of protein tyrosine (Tyr) phosphatases. This review focuses on the development of novel methods for the identification of Ser/Thr phosphatases, especially small C-terminal domain phosphatase 1 (Scp1), using peptide-displayed phage library with AlF₄⁻/BeF₃⁻, and discusses the identification of putative inhibitors. Full article

(This article belongs to the Special Issue Advances of Peptide Engineering)

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