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Cell Reports May 2024The binding and function of β-arrestins are regulated by specific phosphorylation motifs present in G protein-coupled receptors (GPCRs). However, the exact arrangement...
The binding and function of β-arrestins are regulated by specific phosphorylation motifs present in G protein-coupled receptors (GPCRs). However, the exact arrangement of phosphorylated amino acids responsible for establishing a stable interaction remains unclear. We employ a 1D sequence convolution model trained on GPCRs with established β-arrestin-binding properties. With this approach, amino acid motifs characteristic of GPCRs that form stable interactions with β-arrestins can be identified, a pattern that we name "arreSTick." Intriguingly, the arreSTick pattern is also present in numerous non-receptor proteins. Using proximity biotinylation assay and mass spectrometry analysis, we demonstrate that the arreSTick motif controls the interaction between many non-receptor proteins and β-arrestin2. The HIV-1 Tat-specific factor 1 (HTSF1 or HTATSF1), a nuclear transcription factor, contains the arreSTick pattern, and its subcellular localization is influenced by β-arrestin2. Our findings unveil a broader role for β-arrestins in phosphorylation-dependent interactions, extending beyond GPCRs to encompass non-receptor proteins as well.
PubMed: 38758647
DOI: 10.1016/j.celrep.2024.114241 -
Mitochondrial DNA. Part B, Resources 2024Durian, a member of the Malvaceae family, is famous for its delicious fruits, which have strong scents and are rich in nutrients. In this study, we sequenced and...
Durian, a member of the Malvaceae family, is famous for its delicious fruits, which have strong scents and are rich in nutrients. In this study, we sequenced and characterized the complete chloroplast genome of L. 1774 cultivar Ri6, a popular durian cultivar in Vietnam, using the Illumina Hiseq platform. The results showed a circular chloroplast genome composed of a large single copy of 96,115 bp, a small single copy of 20,819 bp, and two inverted repeat regions of 24,185 bp. This genome consisted of 79 protein-coding genes, 30 transfer RNA genes, and four ribosomal RNA genes. The overall GC content of this genome was 35.7%. Phylogenetic analysis inferred from 78 protein-coding regions revealed monophyly of species and a close relationship between cultivar Ri6 and cultivar Mongthong. This study provides essential information for further studies examining genetic population, breedings, and species identification among taxa and cultivars.
PubMed: 38737395
DOI: 10.1080/23802359.2024.2350619 -
International Journal of Molecular... Apr 2024Aging and age-related diseases are associated with a decline in the capacity of protein turnover. Intrinsically disordered proteins, as well as proteins misfolded and...
Aging and age-related diseases are associated with a decline in the capacity of protein turnover. Intrinsically disordered proteins, as well as proteins misfolded and oxidatively damaged, prone to aggregation, are preferentially digested by the ubiquitin-independent proteasome system (UIPS), a major component of which is the 20S proteasome. Therefore, boosting 20S activity constitutes a promising strategy to counteract a decrease in total proteasome activity during aging. One way to enhance the proteolytic removal of unwanted proteins appears to be the use of peptide-based activators of the 20S. In this study, we synthesized a series of peptides and peptidomimetics based on the C-terminus of the Rpt5 subunit of the 19S regulatory particle. Some of them efficiently stimulated human 20S proteasome activity. The attachment of the cell-penetrating peptide TAT allowed them to penetrate the cell membrane and stimulate proteasome activity in HEK293T cells, which was demonstrated using a cell-permeable substrate of the proteasome, TAS3. Furthermore, the best activator enhanced the degradation of aggregation-prone α-synuclein and Tau-441. The obtained compounds may therefore have the potential to compensate for the unbalanced proteostasis found in aging and age-related diseases.
Topics: Humans; Proteasome Endopeptidase Complex; HEK293 Cells; Aging; Protein Aggregates; Proteolysis; alpha-Synuclein; Peptides; tau Proteins; Protein Aggregation, Pathological; Peptidomimetics
PubMed: 38731881
DOI: 10.3390/ijms25094663 -
Molecules (Basel, Switzerland) May 2024Upon a variety of environmental stresses, eukaryotic cells usually recruit translational stalled mRNAs and RNA-binding proteins to form cytoplasmic condensates known as...
Upon a variety of environmental stresses, eukaryotic cells usually recruit translational stalled mRNAs and RNA-binding proteins to form cytoplasmic condensates known as stress granules (SGs), which minimize stress-induced damage and promote stress adaptation and cell survival. SGs are hijacked by cancer cells to promote cell survival and are consequently involved in the development of anticancer drug resistance. However, the design and application of chemical compounds targeting SGs to improve anticancer drug efficacy have rarely been studied. Here, we developed two types of SG inhibitory peptides (SIPs) derived from SG core proteins Caprin1 and USP10 and fused with cell-penetrating peptides to generate TAT-SIP-C1/2 and SIP-U1-Antp, respectively. We obtained 11 SG-inducing anticancer compounds from cell-based screens and explored the potential application of SIPs in overcoming resistance to the SG-inducing anticancer drug sorafenib. We found that SIPs increased the sensitivity of HeLa cells to sorafenib via the disruption of SGs. Therefore, anticancer drugs which are competent to induce SGs could be combined with SIPs to sensitize cancer cells, which might provide a novel therapeutic strategy to alleviate anticancer drug resistance.
Topics: Humans; Sorafenib; Antineoplastic Agents; Stress Granules; HeLa Cells; Drug Resistance, Neoplasm; Peptides; Cell Survival; Ubiquitin Thiolesterase; Neoplasms; Cell Line, Tumor; Cell-Penetrating Peptides
PubMed: 38731625
DOI: 10.3390/molecules29092134 -
Briefings in Bioinformatics Mar 2024Protein acetylation is one of the extensively studied post-translational modifications (PTMs) due to its significant roles across a myriad of biological processes....
Protein acetylation is one of the extensively studied post-translational modifications (PTMs) due to its significant roles across a myriad of biological processes. Although many computational tools for acetylation site identification have been developed, there is a lack of benchmark dataset and bespoke predictors for non-histone acetylation site prediction. To address these problems, we have contributed to both dataset creation and predictor benchmark in this study. First, we construct a non-histone acetylation site benchmark dataset, namely NHAC, which includes 11 subsets according to the sequence length ranging from 11 to 61 amino acids. There are totally 886 positive samples and 4707 negative samples for each sequence length. Secondly, we propose TransPTM, a transformer-based neural network model for non-histone acetylation site predication. During the data representation phase, per-residue contextualized embeddings are extracted using ProtT5 (an existing pre-trained protein language model). This is followed by the implementation of a graph neural network framework, which consists of three TransformerConv layers for feature extraction and a multilayer perceptron module for classification. The benchmark results reflect that TransPTM has the competitive performance for non-histone acetylation site prediction over three state-of-the-art tools. It improves our comprehension on the PTM mechanism and provides a theoretical basis for developing drug targets for diseases. Moreover, the created PTM datasets fills the gap in non-histone acetylation site datasets and is beneficial to the related communities. The related source code and data utilized by TransPTM are accessible at https://www.github.com/TransPTM/TransPTM.
Topics: Acetylation; Protein Processing, Post-Translational; Neural Networks, Computer; Computational Biology; Databases, Protein; Software; Algorithms; Humans; Proteins
PubMed: 38725156
DOI: 10.1093/bib/bbae219 -
RSC Advances May 2024Alchemical binding free energy calculations are one of the most accurate methods for estimating ligand-binding affinity. Assessing the accuracy of the approach over...
Alchemical binding free energy calculations are one of the most accurate methods for estimating ligand-binding affinity. Assessing the accuracy of the approach over protein targets is one of the most interesting issues. The free energy difference of binding between a protein and a ligand was calculated the alchemical approach. The alchemical approach exhibits satisfactory accuracy over four targets, including AmpC beta-lactamase (AmpC); glutamate receptor, ionotropic kainate 1 (GluK1); heat shock protein 90 (Hsp90); and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). In particular, the correlation coefficients between calculated binding free energies and the respective experiments over four targets range from 0.56 to 0.86. The affinity computed free energy perturbation (FEP) simulations is overestimated over the experimental value. Particularly, the electrostatic interaction free energy rules the binding process of ligands to AmpC and GluK1. However, the van der Waals (vdW) interaction free energy plays an important role in the ligand-binding processes of HSP90 and SARS-CoV-2 Mpro. The obtained results associate with the hydrophilic or hydrophobic properties of the ligands. This observation may enhance computer-aided drug design.
PubMed: 38720975
DOI: 10.1039/d4ra00692e -
NeuroImmune Pharmacology and... Mar 2024HIV-1 Tat (transactivator of transcription) protein disrupts dopaminergic transmission and potentiates the rewarding effects of cocaine. Allosteric modulators of the...
OBJECTIVES
HIV-1 Tat (transactivator of transcription) protein disrupts dopaminergic transmission and potentiates the rewarding effects of cocaine. Allosteric modulators of the dopamine transporter (DAT) have been shown to reverse Tat-induced DAT dysfunction. We hypothesized that a novel DAT allosteric modulator, SRI-30827, would counteract Tat-induced potentiation of cocaine reward.
METHODS
Doxycycline (Dox)-inducible Tat transgenic (iTat-tg) mice and their G-tg (Tat-null) counterparts were tested in a cocaine conditioned place preference (CPP) paradigm. Mice were treated 14 days with saline, or Dox (100 mg/kg/day, i.p.) to induce Tat protein. Upon induction, mice were place conditioned two days with cocaine (10 mg/kg/day) after a 1-h daily intracerebroventricular (i.c.v.) pretreatment with SRI-30827 (1 nmol) or a vehicle control, and final place preference assessed as a measure of cocaine reward.
RESULTS
Dox-treatment significantly potentiated cocaine-CPP in iTat-tg mice over the response of saline-treated control littermates. SRI-30827 treatment eliminated Tat-induced potentiation without altering normal cocaine-CPP in saline-treated mice. Likewise, SRI-30827 did not alter cocaine-CPP in both saline- and Dox-treated G-tg mice incapable of expressing Tat protein.
CONCLUSIONS
These findings add to a growing body of evidence that allosteric modulation of DAT could provide a promising therapeutic intervention for patients with comorbid HIV-1 and cocaine use disorder (CUD).
PubMed: 38711842
DOI: 10.1515/nipt-2023-0022 -
Mitochondrial DNA. Part B, Resources 2024Lour. 1790 is a precious medicinal plant species, especially for treating chronic liver diseases. Genomic data on are limited. Therefore, this current study aimed to...
Lour. 1790 is a precious medicinal plant species, especially for treating chronic liver diseases. Genomic data on are limited. Therefore, this current study aimed to characterize the chloroplast genome of and reconstruct the phylogenetic relationship among Helicteroideae taxa. Consequently, the complete chloroplast genome of was 163,404 bp in length and contained 113 unique genes (79 protein-coding genes, 30 tRNA genes, and four rRNA genes). Notably, two introns of gene of were lost in comparison to that of other Helicteroideae species. The phylogenetic tree based on chloroplast genomes of eleven Helicteroideae species revealed that was closely related to species. In conclusion, our study described the first complete chloroplast genome of , which is essential for tracing evolutionary history in the Helicteroideae subfamily.
PubMed: 38707209
DOI: 10.1080/23802359.2024.2345794 -
Frontiers in Microbiology 2024Control of from farm to fork is challenging due to the frequent emergence of antimicrobial-resistant isolates. Furthermore, poultry production systems are known...
INTRODUCTION
Control of from farm to fork is challenging due to the frequent emergence of antimicrobial-resistant isolates. Furthermore, poultry production systems are known reservoirs of . The twin-arginine translocation (Tat) pathway is a crucial bacterial secretion system that allows to colonize the host intestinal tract by using formate as the main source of energy. However, Tat pathway is also a major contributing factor for resistance to copper sulfate (CuSO).
METHODS
Since mammals and chickens do not have proteins or receptors that are homologous to bacterial Tat proteins, identification of small molecule (SM) inhibitors targeting the Tat system would allow the development of safe and effective control methods to mitigate in infected or colonized hosts in both pre-harvest and post-harvest. In this study, we screened 11 commercial libraries ( = 50,917 SM) for increased susceptibility to CuSO (1 mM) in 81-176, a human isolate which is widely studied.
RESULTS
Furthermore, we evaluated 177 SM hits (2.5 μg/mL and above) that increased the susceptibility to CuSO for the inhibition of formate dehydrogenase (Fdh) activity, a Tat-dependent substrate. Eight Tat-dependent inhibitors (T1-T8) were selected for further studies. These selected eight Tat inhibitors cleared all tested strains ( = 12) at >10 ng/mL in the presence of 0.5 mM CuSO. These selected SMs were non-toxic to colon epithelial (Caco-2) cells when treated with 50 μg/mL for 24 h and completely cleared intracellular cells when treated with 0.63 μg/mL of SM for 24 h in the presence of 0.5 mM of CuSO. Furthermore, 3 and 5-week-old chicks treated with SM candidates for 5 days had significantly decreased cecal colonization (up to 1.2 log; < 0.01) with minimal disruption of microbiota. analyses predicted that T7 has better drug-like properties than T2 inhibitor and might target a key amino acid residue (glutamine 165), which is located in the hydrophobic core of TatC protein.
DISCUSSION
Thus, we have identified novel SM inhibitors of the Tat pathway, which represent a potential strategy to control spread on farms.
PubMed: 38694802
DOI: 10.3389/fmicb.2024.1342573 -
Biomedicine & Pharmacotherapy =... Apr 2024Alzheimer's disease (AD) is a global medical challenge. Studies have shown that neurotoxicity caused by pathological aggregation of β-amyloid (Aβ) is an important...
Alzheimer's disease (AD) is a global medical challenge. Studies have shown that neurotoxicity caused by pathological aggregation of β-amyloid (Aβ) is an important factor leading to AD. Therefore, inhibiting the pathological aggregation of Aβ is the key to treating AD. The recombinant human HspB5-ACD structural domain protein (AHspB5) prepared by our group in the previous period has been shown to have anti-amyloid aggregation effects, but its inability to penetrate biological membranes has limited its development. In this study, we prepared a recombinant fusion protein (T-AHspB5) of TAT and AHspB5. In vitro experiments showed that T-AHspB5 inhibited the formation of Aβ protofibrils and had the ability to penetrate the blood-brain barrier; in cellular experiments, T-AHspB5 prevented Aβ-induced oxidative stress damage, apoptosis, and inflammatory responses in neuronal cells, and its mechanism of action was related to microglia activation and mitochondria-dependent apoptotic pathway. In animal experiments, T-AHspB5 improved memory and cognitive dysfunction and inhibited pathological changes of AD in APP/PS1 mice. In conclusion, this paper is expected to reveal the intervention mechanism and biological effect of T-AHspB5 on pathological aggregation of Aβ, provide a new pathway for the treatment of AD, and lay the foundation for the future development and application of T-AHspB5.
PubMed: 38678965
DOI: 10.1016/j.biopha.2024.116661