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Catalytides derived from the Box A region in the ANA/BTG3 protein cleave amyloid-? fragment peptide.

ABSTRACT: We have recently reported about shorter proteolytic peptides termed Catalytide as general name. JAL-TA9 (YKGSGFRMI), a fragment peptide derived from Box A region of Tob1 protein, is the first Catalytide and cleaves A?42 and its fragment peptides. Herein, we demonstrate the enzymatic properties of ANA-TA9 corresponding region to JAL-TA9 in ANA/BTG3 protein. ANA-TA9 showed the auto-proteolytic activity and cleaved 3 kinds of synthetic fragment peptides derived from A?42, especially on the central region of A?42 with a serine protease like activity. Interestingly, 2 kinds of components, ANA-SA5 (SKGQA) and ANA-YA4 (YRMI), also showed similar proteolytic activity. These results indicate that ANA-TA9 is composed of two different Catalytides.

SUBMITTER: Hatakawa Y

PROVIDER: S-EPMC6819762 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Catalytides derived from the Box A region in the ANA/BTG3 protein cleave amyloid-β fragment peptide.

Hatakawa Yusuke Y Nakamura Rina R Konishi Motomi M Sakane Toshiyasu T Saito Motoaki M Akizawa Toshifumi T

Heliyon 20190924 9

We have recently reported about shorter proteolytic peptides termed Catalytide as general name. JAL-TA9 (YKGSGFRMI), a fragment peptide derived from Box A region of Tob1 protein, is the first Catalytide and cleaves Aβ42 and its fragment peptides. Herein, we demonstrate the enzymatic properties of ANA-TA9 corresponding region to JAL-TA9 in ANA/BTG3 protein. ANA-TA9 showed the auto-proteolytic activity and cleaved 3 kinds of synthetic fragment peptides derived from Aβ42, especially on the central ...[more]

PMID: 31687556

Similar Datasets

Amyloid beta cleavage by ANA-TA9, a synthetic peptide from the ANA/BTG3 Box A region.

Project description:IntroductionWe recently discovered a short synthetic peptide derived from the ANA/BTG3 protein Box A region called ANA-TA9 (SKGQAYRMI), which possesses catalytic activity. Herein we demonstrated the proteolytic activity of ANA-TA9 against amyloid beta 42 (Aβ42).MethodsThe proteolytic activity of ANA-TA9 against both the authentic soluble form Aβ42 (a-Aβ42) and the solid insoluble form Aβ42 (s-Aβ42) was analyzed by high-performance liquid chromatography and mass spectrometry. Plasma clearance, brain uptake, and cell viability were examined.ResultsANA-TA9 cleaved not only a-Aβ42 but also s-Aβ42. Proteolytic activity was partially inhibited by 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride, a serine protease inhibitor. Plasma clearance was very rapid, and the brain concentration indicated efficient brain delivery of ANA-TA9 via nasal application. Cell viability analysis indicated that ANA-TA9 did not display toxicity.DiscussionANA-TA9 is an attractive potential candidate for the development of novel peptide drugs in Alzheimer's disease treatment.

| S-EPMC8012241 | biostudies-literature

ASBEL, an ANA/BTG3 antisense transcript required for tumorigenicity of ovarian carcinoma.

Project description:Mammalian genomes encode numerous antisense non-coding RNAs, which are assumed to be involved in the regulation of the sense gene expression. However, the mechanisms of their action and involvement in the development of diseases have not been well elucidated. The ANA/BTG3 protein is an antiproliferative protein whose expression is downregulated in prostate and lung cancers. Here we show that an antisense transcript of the ANA/BTG3 gene, termed ASBEL, negatively regulates the levels of ANA/BTG3 protein, but not of ANA/BTG3 mRNA and is required for proliferation and tumorigenicity of ovarian clear cell carcinoma. We further show that knockdown of ANA/BTG3 rescues growth inhibition caused by ASBEL knockdown. Moreover, we demonstrate that ASBEL forms duplexes with ANA/BTG3 mRNA in the nucleus and suppresses its cytoplasmic transportation. Our findings illustrate a novel function for an antisense transcript that critically promotes tumorigenesis by suppressing translation of the sense gene by inhibiting its cytoplasmic transportation.

| S-EPMC3575586 | biostudies-literature

An apolipoprotein E4 fragment can promote intracellular accumulation of amyloid peptide beta 42.

Project description:Apolipoprotein E (apoE) plays a crucial role in lipid transport in circulation and the brain. The apoE4 isoform is a major risk factor for Alzheimer's disease (AD). ApoE4 is more susceptible to proteolysis than other apoE isoforms and apoE4 fragments have been found in brains of AD patients. These apoE4 fragments have been hypothesized to be involved in the pathogenesis of AD, although the mechanism is not clear. In this study we examined the effect of lipid-free apoE4 on amyloid precursor protein processing and 40-amino-acid Aβ variant and 42-amino-acid Aβ variant levels in human neuroblastoma SK-N-SH cells. We discovered that a specific apoE4 fragment, apoE4[Δ(166-299)], can promote the cellular uptake of extracellular 40-amino-acid Aβ variant and 42-amino-acid Aβ variant either generated after amyloid precursor protein transfection or added exogenously. A longer length fragment, apoE4[Δ(186-299)], or full-length apoE4 failed to elicit this effect. ApoE4[Δ(166-299)] effected a 20% reduction of cellular sphingomyelin levels, as well as changes in cellular membrane micro-fluidity. Following uptake, approximately 50% of 42-amino-acid Aβ variant remained within the cell for at least 24 h, and led to increased formation of reactive oxygen species. Overall, our findings suggest a direct link between two early events in the pathogenesis of AD, apoE4 proteolysis and intraneuronal presence of amyloid beta peptide.

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Microscopic factors that control beta-sheet registry in amyloid fibrils formed by fragment 11-25 of amyloid beta peptide: insights from computer simulations.

Project description:Short fragments of amyloidogenic proteins are widely used as model systems in studies of amyloid formation. Fragment 11-25 of the amyloid beta protein involved in Alzheimer's disease (Abeta11-25) was recently shown to form amyloid fibrils composed of anti-parallel beta-sheets. Interestingly, fibrils grown under neutral and acidic conditions were seen to possess different registries of their inter-beta-strand hydrogen bonds. In an effort to explain the microscopic origin of this pH dependence, we studied Abeta11-25 fibrils using methods of theoretical modeling. Several structural models were built for fibrils at low and neutral pH levels and these were examined in short molecular dynamics simulations in explicit water. The models that displayed the lowest free energy, as estimated using an implicit solvent model, were selected as representative of the true fibrillar structure. It was shown that the registry of these models agrees well with the experimental results. At neutral pH, the main contribution to the free energy difference between the two registries comes from the electrostatic interactions. The charge group of the carboxy terminus makes a large contribution to these interactions and thus appears to have a critical role in determining the registry.

| S-EPMC2696565 | biostudies-literature

Rippled β-Sheet Formation by an Amyloid-β Fragment Indicates Expanded Scope of Sequence Space for Enantiomeric β-Sheet Peptide Coassembly.

Project description:In 1953, Pauling and Corey predicted that enantiomeric β-sheet peptides would coassemble into so-called "rippled" β-sheets, in which the β-sheets would consist of alternating l- and d-peptides. To date, this phenomenon has been investigated primarily with amphipathic peptide sequences composed of alternating hydrophilic and hydrophobic amino acid residues. Here, we show that enantiomers of a fragment of the amyloid-β (Aβ) peptide that does not follow this sequence pattern, amyloid-β (16-22), readily coassembles into rippled β-sheets. Equimolar mixtures of enantiomeric amyloid-β (16-22) peptides assemble into supramolecular structures that exhibit distinct morphologies from those observed by self-assembly of the single enantiomer pleated β-sheet fibrils. Formation of rippled β-sheets composed of alternating l- and d-amyloid-β (16-22) is confirmed by isotope-edited infrared spectroscopy and solid-state NMR spectroscopy. Sedimentation analysis reveals that rippled β-sheet formation by l- and d-amyloid-β (16-22) is energetically favorable relative to self-assembly into corresponding pleated β-sheets. This work illustrates that coassembly of enantiomeric β-sheet peptides into rippled β-sheets is not limited to peptides with alternating hydrophobic/hydrophilic sequence patterns, but that a broader range of sequence space is available for the design and preparation of rippled β-sheet materials.

| S-EPMC6571685 | biostudies-literature

The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers.

Project description:The amyloid beta-peptide (Aβ) plays a leading role in Alzheimer's disease (AD) physiopathology. Even though monomeric forms of Aβ are harmless to cells, Aβ can aggregate into β-sheet oligomers and fibrils, which are both neurotoxic. Therefore, one of the main therapeutic approaches to cure or delay AD onset and progression is targeting Aβ aggregation. In the present study, we show that a pool of human gamma immunoglobulins (IgG) protected cortical neurons from the challenge with Aβ oligomers, as assayed by MTT reduction, caspase-3 activation and cytoskeleton integrity. In addition, we report the inhibitory effect of IgG on Aβ aggregation, as shown by Thioflavin T assay, size exclusion chromatography and atomic force microscopy. Similar results were obtained with Palivizumab, a human anti-sincitial virus antibody. In order to dissect the important domains, we cleaved the pool of human IgG with papain to obtain Fab and Fc fragments. Using these cleaved fragments, we functionally identified Fab as the immunoglobulin fragment inhibiting Aβ aggregation, a result that was further confirmed by an in silico structural model. Interestingly, bioinformatic tools show a highly conserved structure able to bind amyloid in the Fab region. Overall, our data strongly support the inhibitory effect of human IgG on Aβ aggregation and its neuroprotective role.

| S-EPMC5522293 | biostudies-literature

Transcription profiling of rat astrocytes cultured on the beta-amyloid peptide 25-35 fragment for 12 hours, 1, 3 and 5 days

Project description:Cortical type-I astrocytes were cultured on the beta-amyloid peptide 25-35 fragment for 12hr, 1d, 3d, and 5d.

2007-10-12 | E-GEOD-856 | biostudies-arrayexpress

Conformational transition of amyloid beta-peptide.

Project description:The amyloid beta-peptides (Abetas), containing 39-43 residues, are the key protein components of amyloid deposits in Alzheimer's disease. To structurally characterize the dynamic behavior of Abeta(40), 12 independent long-time molecular dynamics (MD) simulations for a total of 850 ns were performed on both the wide-type peptide and its mutant in both aqueous solution and a biomembrane environment. In aqueous solution, an alpha-helix to beta-sheet conformational transition for Abeta(40) was observed, and an entire unfolding process from helix to coil was traced by MD simulation. Structures with beta-sheet components were observed as intermediates in the unfolding pathway of Abeta(40). Four glycines (G(25), G(29), G(33), and G(37)) are important for Abeta(40) to form beta-sheet in aqueous solution; mutations of these glycines to alanines almost abolished the beta-sheet formation and increased the content of the helix component. In the dipalmitoyl phosphatidylcholine (DPPC) bilayer, the major secondary structure of Abeta(40) is a helix; however, the peptide tends to exit the membrane environment and lie down on the surface of the bilayer. The dynamic feature revealed by our MD simulations rationalized several experimental observations for Abeta(40) aggregation and amyloid fibril formation. The results of MD simulations are beneficial to understanding the mechanism of amyloid formation and designing the compounds for inhibiting the aggregation of Abeta and amyloid fibril formation.

| S-EPMC556260 | biostudies-literature

Interaction between amyloid beta peptide and an aggregation blocker peptide mimicking islet amyloid polypeptide.

Project description:Assembly of amyloid-beta peptide (A?) into cytotoxic oligomeric and fibrillar aggregates is believed to be a major pathologic event in Alzheimer's disease (AD) and interfering with A? aggregation is an important strategy in the development of novel therapeutic approaches. Prior studies have shown that the double N-methylated analogue of islet amyloid polypeptide (IAPP) IAPP-GI, which is a conformationally constrained IAPP analogue mimicking a non-amyloidogenic IAPP conformation, is capable of blocking cytotoxic self-assembly of A?. Here we investigate the interaction of IAPP-GI with A?40 and A?42 using NMR spectroscopy. The most pronounced NMR chemical shift changes were observed for residues 13-20, while residues 7-9, 15-16 as well as the C-terminal half of A?--that is both regions of the A? sequence that are converted into ?-strands in amyloid fibrils--were less accessible to solvent in the presence of IAPP-GI. At the same time, interaction of IAPP-GI with A? resulted in a concentration-dependent co-aggregation of A? and IAPP-GI that was enhanced for the more aggregation prone A?42 peptide. On the basis of the reduced toxicity of the A? peptide in the presence of IAPP-GI, our data are consistent with the suggestion that IAPP-GI redirects A? into nontoxic "off-pathway" aggregates.

| S-EPMC3102090 | biostudies-literature

A fragment of the scaffolding protein RanBP9 is increased in Alzheimer's disease brains and strongly potentiates amyloid-beta peptide generation.

Project description:Increasing biochemical and genetic evidence indicates that the amyloid-beta (Abeta) peptide derived from amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD) pathogenesis. We previously reported that RanBP9 promotes Abeta generation by scaffolding APP/BACE1/LRP complexes together. Interestingly, the RanBP9-Delta1/N60 (residues 1-392) deletion mutant interacted much more strongly with APP/BACE1/LRP than full-length RanBP9. In this study, we found that RanBP9-N60, a processed form of RanBP9 virtually identical to the RanBP9-Delta1/N60 mutant, was strongly increased in AD brains compared with controls. To evaluate the potential pathogenic consequences of this phenotype, we studied the differential biological properties of full-length RanBP9 vs. RanBP9-Delta1/N60 in HEK293T and Neuro-2A cells. The RanBP9-Delta1/N60 fragment, which lacks a nuclear localization signal, displayed enhanced cytoplasmic vs. nuclear localization and >3-fold enhanced stability than full-length RanBP9. Importantly, RanBP9-Delta1/N60, which contains the LisH dimerization domain, retained the capacity to form self-interacting multimeric complexes and increased Abeta generation by approximately 5-fold over vector controls, more potent than the approximately 3-fold increase seen by full-length RanBP9. Taken together, these data indicate that RanBP9-N60 may further drive the amyloid cascade in AD and that the proteolytic processing of RanBP9 may be an attractive therapeutic target.

| S-EPMC2797034 | biostudies-literature

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