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1.
Food Chem ; 400: 134057, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36075173

RESUMO

Mechanical damage caused by vibration during transportation can destroy organization structure and reduce the fruit quality. The objective was to reveal the mechanism of hypobaric treatment on energy metabolism in vibration-injured 'Huangguan' pears based on metabolomics. Results showed that hypobaric treatment delayed the decline of adenosine triphosphate (ATP) content, energy charge (EC), H+-ATPase and Ca2+-ATPase activities comparing to untreated samples. Metabolomics data indicated there were 83 significant differential metabolites between untreated samples and hypobaric treated ones. KEGG analysis results showed significant differential metabolites were associated with 14 pathways. Key metabolites and pathways analysis revealed these up-regulated amino acids were related to amino acid metabolism, biosynthesis of secondary metabolites and membrane transport. These pathways were activated observably by hypobaric treatment. The results indicated hypobaric treatment slowed energy consumption in vibration-injured samples, which was in relation to the accumulation of amino acids. The findings provide a feasible preservation technology for vibration-injured fruit.


Assuntos
Pyrus , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Aminoácidos/metabolismo , Metabolismo Energético , Metabolômica/métodos , Pyrus/metabolismo , Vibração
2.
Food Chem ; 400: 133996, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36055140

RESUMO

24-Epibrassinolide (EBR) may act as a modulator for chilling injury in peach fruit during cold storage. In this study, we screened a EBR-induced GATA-type zinc finger protein PpGATA12. The objective of this study was to investigate the potential roles of EBR treatment and transcriptional regulation of PpGATA12 in regulating chilling resistance of peaches. In the current study, we found that EBR treatment promoted the activities and transcriptions of energy and sucrose metabolism-related enzymes, maintained higher ATP content and energy status, improved the accumulation of sucrose and hexose. Furthermore, molecular biology assays suggested that PpGATA12 up-regulated transcriptions of sucrose metabolism-related genes including PpSS and PpNI, and energy metabolism-related genes including PpCCO, PpSDH and PpH+-ATPase. These results provided a new insight that the enhancement of chilling resistance in peach fruit by EBR treatment might be closely related to the regulatory role of PpGATA12 on sucrose and energy metabolisms.


Assuntos
Prunus persica , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Brassinosteroides , Temperatura Baixa , Metabolismo Energético , Frutas/genética , Frutas/metabolismo , Prunus persica/genética , Prunus persica/metabolismo , Esteroides Heterocíclicos , Sacarose/metabolismo
3.
Food Chem ; 399: 133914, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36029673

RESUMO

This work studied the effects of electromagnetic fields (EMF) with frequencies between 100 and 400 Hz and a fixed strength of 12 mT on cold storage of grass carp at 4 °C for 30 min, and Ca2+ATPase enzyme activities, and lipid and protein oxidations in samples were measured to assess changes in intracellular Ca2+ concentration and oxidative stability. Results showed higher Ca2+ATPase activities in samples treated with EMF frequencies. Significant (p < 0.05) decreases occurred in protein oxidation for samples treated between 100 and 300 Hz, but an increase was observed for treatment with 400 Hz. However, the lipid oxidation increased for samples treated up to 200 Hz and decreased with further increase in frequency to 300 and 400 Hz. Nuclear magnetic resonance analysis showed that exposure to different frequencies of EMF could reduce the association of water molecules with protein for both bound and immobilized water. Overall, treatments of EMF between 100 and 400 Hz could improve grass carp quality during cold storage.


Assuntos
Carpas , Adenosina Trifosfatases , Animais , Campos Eletromagnéticos , Lipídeos , Água
4.
Food Chem ; 398: 133885, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-35973299

RESUMO

This work studied the difference in pulp breakdown between two cultivars of longan cv. 'Dongbi' and 'Fuyan' from the aspect of metabolisms of lipid and energy. The results reflected that, compared to 'Fuyan' longan, 'Dongbi' longan had higher levels of energy charge, U/S and IUFA, and higher amounts of USFA, PC, PI, ATP and ADP. Moreover, 'Dongbi' longan exhibited lower levels of SFA, PA, AMP and cell membrane permeability. Also, lower PLD, LOX and lipase activities, but higher ATPase activity, lower pulp breakdown index, and better pulp appearance were exhibited in 'Dongbi' longan. These data revealed that the mitigated pulp breakdown in 'Dongbi' longan was due to the comprehensive coordination of metabolisms in lipid and energy through maintaining a higher level of energy, a higher unsaturation degree of fatty acids, delaying the degradation of phospholipids, and better retaining the membrane structural integrity of microsome and entire cell.


Assuntos
Frutas , Sapindaceae , Adenosina Trifosfatases/metabolismo , Frutas/química , Fosfolipídeos/análise , Sapindaceae/metabolismo
5.
Sci Rep ; 12(1): 15663, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123435

RESUMO

The lack of targeted therapies for triple-negative breast cancer (TNBC) contributes to their high mortality rates and high risk of relapse compared to other subtypes of breast cancer. Most TNBCs (75%) have downregulated the expression of CREB3L1 (cAMP-responsive element binding protein 3 like 1), a transcription factor and metastasis suppressor that represses genes that promote cancer progression and metastasis. In this report, we screened an FDA-approved drug library and identified four drugs that were highly cytotoxic towards HCC1806 CREB3L1-deficient TNBC cells. These four drugs were: (1) palbociclib isethionate, a CDK4/6 inhibitor, (2) lanatocide C (also named isolanid), a Na+/K+-ATPase inhibitor, (3) cladribine, a nucleoside analog, and (4) homoharringtonine (also named omacetaxine mepesuccinate), a protein translation inhibitor. Homoharringtonine consistently showed the most cytotoxicity towards an additional six TNBC cell lines (BT549, HCC1395, HCC38, Hs578T, MDA-MB-157, MDA-MB-436), and several luminal A breast cancer cell lines (HCC1428, MCF7, T47D, ZR-75-1). All four drugs were then separately evaluated for possible synergy with the chemotherapy agents, doxorubicin (an anthracycline) and paclitaxel (a microtubule stabilizing agent). A strong synergy was observed using the combination of homoharringtonine and paclitaxel, with high cytotoxicity towards TNBC cells at lower concentrations than when each was used separately.


Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Adenosina Trifosfatases , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cladribina/uso terapêutico , Doxorrubicina/uso terapêutico , Excipientes , Mepesuccinato de Omacetaxina/farmacologia , Humanos , Nucleosídeos/uso terapêutico , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Neoplasias de Mama Triplo Negativas/patologia
6.
Nat Commun ; 13(1): 5502, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127320

RESUMO

Enteric bacteria have to adapt to environmental stresses in the human gastrointestinal tract such as acid and nutrient stress, oxygen limitation and exposure to antibiotics. Membrane lipid composition has recently emerged as a key factor for stress adaptation. The E. coli ravA-viaA operon is essential for aminoglycoside bactericidal activity under anaerobiosis but its mechanism of action is unclear. Here we characterise the VWA domain-protein ViaA and its interaction with the AAA+ ATPase RavA, and find that both proteins localise at the inner cell membrane. We demonstrate that RavA and ViaA target specific phospholipids and subsequently identify their lipid-binding sites. We further show that mutations abolishing interaction with lipids restore induced changes in cell membrane morphology and lipid composition. Finally we reveal that these mutations render E. coli gentamicin-resistant under fumarate respiration conditions. Our work thus uncovers a ravA-viaA-based pathway which is mobilised in response to aminoglycosides under anaerobiosis and engaged in cell membrane regulation.


Assuntos
Proteínas de Escherichia coli , Escherichia coli , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Adenosina Trifosfatases/metabolismo , Aminoglicosídeos/farmacologia , Antibacterianos/farmacologia , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Fumaratos , Gentamicinas , Humanos , Lipídeos de Membrana , Oxigênio/metabolismo , Fosfolipídeos
7.
Cell Rep ; 40(12): 111379, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36130523

RESUMO

Disruption of the nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) have been implicated in the pathogenesis of neurodegenerative diseases. A GGGGCC hexanucleotide repeat expansion (HRE) in an intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, but the mechanism by which the HRE disrupts NCT is incompletely understood. We find that expression of GGGGCC repeats in Drosophila neurons induces proteasome-mediated degradation of select nucleoporins of the NPC. This process requires the Vps4 ATPase and the endosomal-sorting complex required for transport complex-III (ESCRT-III), as knockdown of ESCRT-III/Vps4 genes rescues nucleoporin levels, normalizes NCT, and suppresses GGGGCC-mediated neurodegeneration. GGGGCC expression upregulates nuclear ESCRT-III/Vps4 expression, and expansion microscopy demonstrates that the nucleoporins are translocated into the cytoplasm before undergoing proteasome-mediated degradation. These findings demonstrate a mechanism for nucleoporin degradation and NPC dysfunction in neurodegenerative disease.


Assuntos
Esclerose Amiotrófica Lateral , Proteínas de Drosophila , Demência Frontotemporal , Doenças Neurodegenerativas , Adenosina Trifosfatases/metabolismo , Esclerose Amiotrófica Lateral/metabolismo , Animais , Proteína C9orf72/genética , Expansão das Repetições de DNA , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Demência Frontotemporal/metabolismo , Doenças Neurodegenerativas/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Regulação para Cima/genética
8.
Elife ; 112022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36062913

RESUMO

Three-component ParABS partition systems ensure stable inheritance of many bacterial chromosomes and low-copy-number plasmids. ParA localizes to the nucleoid through its ATP-dependent nonspecific DNA-binding activity, whereas centromere-like parS-DNA and ParB form partition complexes that activate ParA-ATPase to drive the system dynamics. The essential parS sequence arrangements vary among ParABS systems, reflecting the architectural diversity of their partition complexes. Here, we focus on the pSM19035 plasmid partition system that uses a ParBpSM of the ribbon-helix-helix (RHH) family. We show that parSpSM with four or more contiguous ParBpSM-binding sequence repeats is required to assemble a stable ParApSM-ParBpSM complex and efficiently activate the ParApSM-ATPase, stimulating complex disassembly. Disruption of the contiguity of the parSpSM sequence array destabilizes the ParApSM-ParBpSM complex and prevents efficient ATPase activation. Our findings reveal the unique architecture of the pSM19035 partition complex and how it interacts with nucleoid-bound ParApSM-ATP.


Assuntos
Adenosina Trifosfatases , Proteínas de Bactérias , Adenosina Trifosfatases/química , Adenosina Trifosfatases/genética , Trifosfato de Adenosina/química , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Centrômero , DNA , DNA Bacteriano/química , DNA Bacteriano/genética , Plasmídeos
9.
PLoS Comput Biol ; 18(9): e1010494, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36067222

RESUMO

When the mixture solution of cyanobacterial proteins, KaiA, KaiB, and KaiC, is incubated with ATP in vitro, the phosphorylation level of KaiC shows stable oscillations with the temperature-compensated circadian period. Elucidating this temperature compensation is essential for understanding the KaiABC circadian clock, but its mechanism has remained a mystery. We analyzed the KaiABC temperature compensation by developing a theoretical model describing the feedback relations among reactions and structural transitions in the KaiC molecule. The model showed that the reduced structural cooperativity should weaken the negative feedback coupling among reactions and structural transitions, which enlarges the oscillation amplitude and period, explaining the observed significant period extension upon single amino-acid residue substitution. We propose that an increase in thermal fluctuations similarly attenuates the reaction-structure feedback, explaining the temperature compensation in the KaiABC clock. The model explained the experimentally observed responses of the oscillation phase to the temperature shift or the ADP-concentration change and suggested that the ATPase reactions in the CI domain of KaiC affect the period depending on how the reaction rates are modulated. The KaiABC clock provides a unique opportunity to analyze how the reaction-structure coupling regulates the system-level synchronized oscillations of molecules.


Assuntos
Relógios Circadianos , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano , Difosfato de Adenosina/metabolismo , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Proteínas de Bactérias/metabolismo , Relógios Circadianos/fisiologia , Ritmo Circadiano , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Fosforilação , Temperatura
10.
Appl Environ Microbiol ; 88(18): e0140322, 2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-36094177

RESUMO

Type IV pili (Tfp) are known to mediate several biological activities, including surface-dependent twitching motility. Although a pil gene cluster for Tfp biosynthesis is found in all sequenced Streptococcus sanguinis strains, Tfp-mediated twitching motility is less commonly detected. Upon examining 81 clinical strains, 39 strains generated twitching zones on blood agar plates (BAP), while 27 strains displayed twitching on Todd-Hewitt (TH) agar. Although BAP appears to be more suitable for the development of twitching zones, 5 strains exhibited twitching motility only on TH agar, indicating that twitching motility is not only strain specific but also sensitive to growth media. Furthermore, different twitching phenotypes were observed in strains expressing comparable levels of pilT, encoding the retraction ATPase, suggesting that the twitching phenotype on agar plates is regulated by multiple factors. By using a PilT-null and a pilin protein-null derivative (CHW02) of twitching-active S. sanguinis CGMH010, we found that Tfp retraction was essential for biofilm stability. Further, biofilm growth was amplified in CHW02 in the absence of shearing force, indicating that S. sanguinis may utilize other ligands for biofilm formation in the absence of Tfp. Similar to SK36, Tfp from CGMH010 were required for colonization of host cells, but PilT only marginally affected adherence and only in the twitching-active strain. Taken together, the results suggest that Tfp participates in host cell adherence and that Tfp retraction facilitates biofilm stability. IMPORTANCE Although the gene clusters encoding Tfp are commonly present in Streptococcus sanguinis, not all strains express surface-dependent twitching motility on agar surfaces. Regardless of whether the Tfp could drive motility, Tfp can serve as a ligand for the colonization of host cells. Though many S. sanguinis strains lack twitching activity, motility can enhance biofilm stability in a twitching-active strain; thus, perhaps motility provides little or no advantage to the survival of bacteria within dental plaque. Rather, Tfp retraction could provide additional advantages for the bacteria to establish infections outside the oral cavity.


Assuntos
Proteínas de Fímbrias , Streptococcus sanguis , Adenosina Trifosfatases/metabolismo , Ágar/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biofilmes , Proteínas de Fímbrias/genética , Fímbrias Bacterianas/genética , Fímbrias Bacterianas/metabolismo , Ligantes , Prevalência , Streptococcus sanguis/genética , Streptococcus sanguis/metabolismo
11.
Toxicon ; 218: 57-65, 2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36113683

RESUMO

Rhinella marina toad is abundant in Brazil. Its poison contains cardiac glycosides called bufadienolides, which are extensively investigated for their bioactivity. Our aim was to characterize the vasoactivity of Rhinella marina poison (RmP) on the aorta of male Wistar rats. For this, the RmP was first collected and processed to obtain an alcoholic extract. To determine cardiovascular effects of RmP, we performed in vivo tests by administering RmP intravenously in doses of 0.1-0.8 mg/kg. Vascular reactivity was also performed through concentration-response curves to RmP (10 ng/mL to 200 µg/mL) in aortic segments with and without endothelium. RmP induced a concentration-dependent contraction in rat aorta which was partly endothelium-mediated. Nitric oxide contributes with this response in view that incubation with L-NAME increased the contractile response. Additionally, treatment with indomethacin [cyclooxygenase, (COX) inhibitor], nifedipine (L-type voltage-gated calcium channels blocker), and BQ-123 (ETA receptors antagonist) decreased maximum response, and ketanserin (5-HT2 receptors antagonist) decreased pEC50, suggesting active participation of these pathways in the contractile response. On the other hand, apocynin (NADPH oxidase inhibitor) did not alter contractility. Incubation with prazosin (α1-adrenergic receptor antagonist) abolished the contractile response, suggesting that the RmP-induced contraction is dependent on the adrenergic pathway. In the Na+/K+ ATPase protocol, a higher Emax was observed in the RmP experimental group, suggesting that RmP potentiated Na+/K+ATPase hyperpolarizing response. When this extract was injected (i.v.) in vivo, increase in blood pressure and decrease in heart rate were observed. The results were immediate and transitory, and occurred in a dose-dependent manner. Overall, these data suggest that the poison extract of R. marina toad has an important vasoconstrictor action and subsequent vasopressor effects, and its use can be investigated to some cardiovascular disorders.


Assuntos
Bufanolídeos , Venenos , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/farmacologia , Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/farmacologia , Animais , Bufanolídeos/toxicidade , Bufo marinus/metabolismo , Canais de Cálcio , Endotélio Vascular , Hemodinâmica , Indometacina/farmacologia , Ketanserina/farmacologia , Masculino , Metanol/farmacologia , NADPH Oxidases , NG-Nitroarginina Metil Éster , Nifedipino/farmacologia , Óxido Nítrico/metabolismo , Prazosina/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos , Ratos Wistar , Serotonina/farmacologia , Vasoconstritores
12.
Eur J Pharmacol ; 932: 175237, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36063871

RESUMO

Increasing evidence indicates that hyperuricaemia (HUA) is not only a result of decreased renal urate excretion but also a contributor to kidney disease. Na+-K+-ATPase (NKA), which establishes the sodium gradient for urate transport in proximal tubular epithelial cells (PTECs), its impairment leads to HUA-induced nephropathy. However, the specific mechanism underlying NKA impairment-mediated renal tubular injury and increased urate reabsorption in HUA is not well understood. In this study, we investigated whether autophagy plays a key role in the NKA impairment signalling and increased urate reabsorption in HUA-induced renal tubular injury. Protein spectrum analysis of exosomes from the urine of HUA patients revealed the activation of lysosomal processes, and exosomal expression of lysosomal-associated membrane protein-2 was associated with increased serum levels and decreased renal urate excretion in patients. We demonstrated that high uric acid (UA) induced lysosome dysfunction, autophagy and inflammation in a time- and dose-dependent manner and that high UA and/or NKA α1 siRNA significantly increased mitochondrial abnormalities, such as reductions in mitochondrial respiratory complexes and cellular ATP levels, accompanied by increased apoptosis in cultured PTECs. The autophagy inhibitor hydroxychloroquine (HCQ) ameliorated NKA impairment-mediated mitochondrial dysfunction, Nod-like receptor pyrin domain-containing protein 3 (NLRP3)-interleukin-1ß (IL-1ß) production, and abnormal urate reabsorption in PTECs stimulated with high UA and in rats with oxonic acid (OA)-induced HUA. Our findings suggest that autophagy plays a pivotal role in NKA impairment-mediated signalling and abnormal urate reabsorption in HUA-induced renal tubular injury and that inhibition of autophagy by HCQ could be a promising treatment for HUA.


Assuntos
Hiperuricemia , Adenosina Trifosfatases , Trifosfato de Adenosina , Animais , Autofagia , Hidroxicloroquina , Hiperuricemia/complicações , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Interleucina-1beta , Glicoproteínas de Membrana Associadas ao Lisossomo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ácido Oxônico , RNA Interferente Pequeno , Ratos , Ratos Sprague-Dawley , Sódio , ATPase Trocadora de Sódio-Potássio , Ácido Úrico/metabolismo
13.
Ecotoxicol Environ Saf ; 244: 114038, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36075120

RESUMO

Cypermethrin contamination was a potential threat to soil organisms. In the present work, reproductive damage in earthworms (Amynthas corticis) exposed to cypermethrin was investigated. It was found that earthworms could absorb and accumulate residual cypermethrin in soil, and also earthworm activities helped accelerate the degradation of cypermethrin in soil. The accumulation of cypermethrin in earthworms induced sperm damage, and cypermethrin not only caused the imbalance of calcium homeostasis in earthworm sperm cells by inhibiting earthworm sperm Ca2+-ATP and Ca2+-Mg2+-ATP enzyme activities but also caused barriers in acrosome reaction. It also affected sperm energy supply of earthworms by inhibiting the activity of Na+-K+-ATPase and Mg2+-ATPase of earthworm sperm. Meanwhile, the inhibition of acrosome enzyme activity of earthworm sperm by cypermethrin led to hinder fertilization and reduced cocoon production of earthworms, and the damage of cypermethrin to sperm of earthworm was a significant cause of its reproductive toxicity. The results of the evaluation of IBR index showed that reproductive toxicity of cypermethrin to earthworms reduced with the increasing time. The decreased reproductive toxicity of cypermethrin to earthworms at the later stage of exposure (42-56 d) might be due to a combination of reduced absorption of cypermethrin in soil by earthworms, decreased accumulation of cypermethrin in the body, and improved sperm capacitation.


Assuntos
Oligoquetos , Poluentes do Solo , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Masculino , Oligoquetos/metabolismo , Piretrinas , Sêmen/química , Solo , Poluentes do Solo/análise
14.
BMC Mol Cell Biol ; 23(1): 39, 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36088301

RESUMO

BACKGROUND: The AAA + ATPase p97 is an essential unfoldase/segragase involved in a multitude of cellular processes. It functions as a molecular machine critical for protein homeostasis, homotypic membrane fusion events and organelle biogenesis during mitosis in which it acts in concert with cofactors p47 and p37. Cofactors assist p97 in extracting and unfolding protein substrates through ATP hydrolysis. In contrast to other p97's cofactors, p37 uniquely increases the ATPase activity of p97. Disease-causing mutations in p97, including mutations that cause neurodegenerative diseases, increase cofactor association with its N-domain, ATPase activity and improper substrate processing. Upregulation of p97 has also been observed in various cancers. This study aims towards the characterization of the protein-protein interaction between p97 and p37 at the atomic level. We defined the interacting residues in p97 and p37. The knowledge will facilitate the design of unique small molecules inhibiting this interaction with insights into cancer therapy and drug design. RESULTS: The homology model of human p37 UBX domain was built from the X-ray crystal structure of p47 C-terminus from rat (PDB code:1S3S, G) as a template and assessed by model validation analysis. According to the HDOCK, HAWKDOCK, MM-GBSA binding free energy calculations and Arpeggio, we found that there are several hydrophobic and two hydrogen-bonding interactions between p37 UBX and p97 N-D1 domain. Residues of p37 UBX predicted to be involved in the interactions with p97 N-D1 domain interface are highly conserved among UBX cofactors. CONCLUSION: This study provides a reliable structural insight into the p37-p97 complex binding sites at the atomic level though molecular docking coupled with molecular dynamics simulation. This can guide the rational design of small molecule drugs for inhibiting mutant p97 activity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , Adenosina Trifosfatases , Simulação de Dinâmica Molecular , Proteína com Valosina/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Humanos , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Ratos , Proteína com Valosina/metabolismo
15.
Nat Struct Mol Biol ; 29(9): 942-953, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36097293

RESUMO

The AAA-ATPase Drg1 is a key factor in eukaryotic ribosome biogenesis that initiates cytoplasmic maturation of the large ribosomal subunit. Drg1 releases the shuttling maturation factor Rlp24 from pre-60S particles shortly after nuclear export, a strict requirement for downstream maturation. The molecular mechanism of release remained elusive. Here, we report a series of cryo-EM structures that captured the extraction of Rlp24 from pre-60S particles by Saccharomyces cerevisiae Drg1. These structures reveal that Arx1 and the eukaryote-specific rRNA expansion segment ES27 form a joint docking platform that positions Drg1 for efficient extraction of Rlp24 from the pre-ribosome. The tips of the Drg1 N domains thereby guide the Rlp24 C terminus into the central pore of the Drg1 hexamer, enabling extraction by a hand-over-hand translocation mechanism. Our results uncover substrate recognition and processing by Drg1 step by step and provide a comprehensive mechanistic picture of the conserved modus operandi of AAA-ATPases.


Assuntos
Proteínas de Saccharomyces cerevisiae , ATPases Associadas a Diversas Atividades Celulares , Adenosina Trifosfatases/metabolismo , Proteínas Ribossômicas/metabolismo , Subunidades Ribossômicas Maiores de Eucariotos/metabolismo , Ribossomos/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
16.
Nat Struct Mol Biol ; 29(9): 922-931, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36097294

RESUMO

In addition to its role in chromosome maintenance, the six-membered Smc5/6 complex functions as a restriction factor that binds to and transcriptionally silences viral and other episomal DNA. However, the underlying mechanism is unknown. Here, we show that transcriptional silencing by the human Smc5/6 complex is a three-step process. The first step is entrapment of the episomal DNA by a mechanism dependent on Smc5/6 ATPase activity and a function of its Nse4a subunit for which the Nse4b paralog cannot substitute. The second step results in Smc5/6 recruitment to promyelocytic leukemia nuclear bodies by SLF2 (the human ortholog of Nse6). The third step promotes silencing through a mechanism requiring Nse2 but not its SUMO ligase activity. By contrast, the related cohesin and condensin complexes fail to bind to or silence episomal DNA, indicating a property unique to Smc5/6.


Assuntos
Proteínas de Ciclo Celular , Sumoilação , Adenosina Trifosfatases/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , DNA/metabolismo , Reparo do DNA , Humanos , Ligases/genética , Ligases/metabolismo
17.
Int J Mol Sci ; 23(18)2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36142525

RESUMO

Heat stress that occurs during the flowering stage severely decreases the rice (Oryza sativa L.) seed-setting rate. This damage can be reversed by abscisic acid (ABA), through effects on reactive oxygen species, carbohydrate metabolism, and heat shock proteins, but the exact role of trehalose and ATP in this process remains unclear. Two rice genotypes, namely, Zhefu802 (heat-resistant plant, a recurrent parent) and its near-isogenic line (faded green leaf, Fgl, heat-sensitive plant), were subjected to 38 °C heat stress after being sprayed with ABA or its biosynthetic inhibitor, fluridone (Flu), at the flowering stage. The results showed that exogenous ABA significantly increased the seed-setting rate of rice under heat stress, by 14.31 and 22.40% in Zhefu802 and Fgl, respectively, when compared with the H2O treatment. Similarly, exogenous ABA increased trehalose content, key enzyme activities of trehalose metabolism, ATP content, and F1Fo-ATPase activity. Importantly, the opposite results were observed in plants treated with Flu. Therefore, ABA may improve rice thermo-tolerance by affecting trehalose metabolism and ATP consumption.


Assuntos
Ácido Abscísico , Oryza , Ácido Abscísico/metabolismo , Ácido Abscísico/farmacologia , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Metabolismo dos Carboidratos , Regulação da Expressão Gênica de Plantas , Proteínas de Choque Térmico/metabolismo , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estresse Fisiológico , Trealose/metabolismo
18.
Int J Mol Sci ; 23(18)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36142643

RESUMO

Proton pump inhibitors (PPIs) are an antacid drug often used in acid-related disorders. They decrease acid secretion in the stomach by blocking an enzyme called H+/K+ ATPase which controls acid production. Introduced to the market in 1989, their use has increased rapidly worldwide and they are now among the top 10 most prescribed drugs in the United States. As of 2015, the FDA has already approved six drugs of this class (omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole and rabeprazole). Recently, the risks and benefits of long-term PPI use were questioned and many studies indicated that their use should be carefully considered, especially in young patients, whose treatment with these drugs could last many years. Even greater concerns have been raised about a potential positive association between PPIs and osteoporotic fracture risk including the hip, spine and wrist. Although based on observational studies, there is substantial evidence associating the long-term use of PPIs and fracture. This relationship is only partially admitted due to the lack of consistent effects of PPIs on bone mineral density loss. Therefore, this narrative review aimed to discuss the recent findings pertaining to the risk of osteoporotic fracture associated with PPIs, in particular prolonged use, and to call for further research to elucidate the mechanisms associated with this bone fragility.


Assuntos
Fraturas por Osteoporose , Inibidores da Bomba de Prótons , 2-Piridinilmetilsulfinilbenzimidazóis , Adenosina Trifosfatases , Antiácidos , Densidade Óssea , Dexlansoprazol , Esomeprazol , Humanos , Lansoprazol , Omeprazol/farmacologia , Fraturas por Osteoporose/tratamento farmacológico , Pantoprazol , Inibidores da Bomba de Prótons/efeitos adversos , Rabeprazol , Estados Unidos
19.
Int J Mol Sci ; 23(18)2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36142700

RESUMO

Serratia proteamaculans synthesizes the intracellular metalloprotease protealysin. This work was aimed at searching for bacterial substrates of protealysin among the proteins responsible for replication and cell division. We have shown that protealysin unlimitedly cleaves the SOS response protein RecA. Even 20% of the cleaved RecA in solution appears to be incorporated into the polymer of uncleaved monomers, preventing further polymerization and inhibiting RecA ATPase activity. Transformation of Escherichia coli with a plasmid carrying the protealysin gene reduces the bacterial UV survival up to 10 times. In addition, the protealysin substrate is the FtsZ division protein, found in both E. coli and Acholeplasma laidlawii, which is only 51% identical to E. coli FtsZ. Protealysin cleaves FtsZ at the linker between the globular filament-forming domain and the C-terminal peptide that binds proteins on the bacterial membrane. Thus, cleavage of the C-terminal segment by protealysin can lead to the disruption of FtsZ's attachment to the membrane, and thereby inhibit bacterial division. Since the protealysin operon encodes not only the protease, but also its inhibitor, which is typical for the system of interbacterial competition, we assume that in the case of penetration of protealysin into neighboring bacteria that do not synthesize a protealysin inhibitor, cleavage of FtsZ and RecA by protealysin may give S. proteamaculans an advantage in interbacterial competition.


Assuntos
Proteínas de Bactérias , Proteínas de Escherichia coli , Adenosina Trifosfatases/metabolismo , Proteínas de Bactérias/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Trabalho Doméstico , Metaloproteases/metabolismo , Peptídeo Hidrolases/metabolismo , Peptídeos/química , Polímeros/metabolismo
20.
Mar Environ Res ; 180: 105736, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36049432

RESUMO

Triphenyltin (TPT) has attracted considerable attention owing to its vitality, bioaccumulation, and lurking damage. TPT widely exists in complex salinity areas such as estuaries and coastal regions. However, there are few studies on the toxicological behavior of TPT under different salinity. In the study, juvenile Nile tilapia (Oreochromis niloticus) were utilized as model animals to investigate the effects of environmental relevant TPT exposure on the osmoregulation and energy metabolism in gill under different salinity. The results showed that salinity and TPT single or combined exposure affected the morphology of the gill tissue. After TPT exposure, Na+-K+-ATPase (NKA) activity significantly decreased at 0 ppt, while NKA and Ca2+-Mg2+-ATPase (CMA) activities significantly increased at 15 ppt. In addition, significantly higher succinate dehydrogenase (SDH) and lactate dehydrogenase (LDH) activities were found in the control fish compared to the TPT-exposed ones at 15 ppt. Quantitative real-time PCR results showed that TPT exposure affected the expression of osmoregulation and energy metabolism-related genes under different salinity. Overall, TPT exposure interfered with osmoregulation and energy metabolism under different salinity. The study will provide reference data for assessing the toxicity of organotin compounds in complex-salinity areas.


Assuntos
Ciclídeos , Compostos Orgânicos de Estanho , Adenosina Trifosfatases/metabolismo , Animais , Ciclídeos/metabolismo , Brânquias/metabolismo , Compostos Orgânicos de Estanho/metabolismo , Compostos Orgânicos de Estanho/toxicidade , Salinidade
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