CRDs
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Transcription factor p53 protects cells against tumorigenesis when subjected to various cellular stresses. Under these conditions, p53 interacts with transcription factor Forkhead box O (FOXO) 4, thereby inducing cellular senescence by upregulating the transcription of senescence-associated protein p21. However, the structural details of this interaction remain unclear. Here, we characterize the interaction between p53 and FOXO4 by NMR, chemical cross-linking, and analytical ultracentrifugation. Our results reveal that the interaction between p53 TAD and the FOXO4 Forkhead domain is essential for the overall stability of the p53:FOXO4 complex. Furthermore, contacts involving the N-terminal segment of FOXO4, the C-terminal negative regulatory domain of p53 and the DNA-binding domains of both proteins stabilize the complex, whose formation blocks p53 binding to DNA but without affecting the DNA-binding properties of FOXO4. Therefore, our structural findings may help to understand the intertwined functions of p53 and FOXO4 in cellular homeostasis, longevity, and stress response.
BACKGROUND: Updated data on chronic respiratory diseases (CRDs) are vital in their prevention, control, and treatment in the path to achieving the third UN Sustainable Development Goals (SDGs), a one-third reduction in premature mortality from non-communicable diseases by 2030. We provided global, regional, and national estimates of the burden of CRDs and their attributable risks from 1990 to 2019. METHODS: Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we estimated mortality, years lived with disability, years of life lost, disability-adjusted life years (DALYs), prevalence, and incidence of CRDs, i.e. chronic obstructive pulmonary disease (COPD), asthma, pneumoconiosis, interstitial lung disease and pulmonary sarcoidosis, and other CRDs, from 1990 to 2019 by sex, age, region, and Socio-demographic Index (SDI) in 204 countries and territories. Deaths and DALYs from CRDs attributable to each risk factor were estimated according to relative risks, risk exposure, and the theoretical minimum risk exposure level input. FINDINGS: In 2019, CRDs were the third leading cause of death responsible for 4.0 million deaths (95% uncertainty interval 3.6-4.3) with a prevalence of 454.6 million cases (417.4-499.1) globally. While the total deaths and prevalence of CRDs have increased by 28.5% and 39.8%, the age-standardised rates have dropped by 41.7% and 16.9% from 1990 to 2019, respectively. COPD, with 212.3 million (200.4-225.1) prevalent cases, was the primary cause of deaths from CRDs, accounting for 3.3 million (2.9-3.6) deaths. With 262.4 million (224.1-309.5) prevalent cases, asthma had the highest prevalence among CRDs. The age-standardised rates of all burden measures of COPD, asthma, and pneumoconiosis have reduced globally from 1990 to 2019. Nevertheless, the age-standardised rates of incidence and prevalence of interstitial lung disease and pulmonary sarcoidosis have increased throughout this period. Low- and low-middle SDI countries had the highest age-standardised death and DALYs rates while the high SDI quintile had the highest prevalence rate of CRDs. The highest deaths and DALYs from CRDs were attributed to smoking globally, followed by air pollution and occupational risks. Non-optimal temperature and high body-mass index were additional risk factors for COPD and asthma, respectively. INTERPRETATION: Albeit the age-standardised prevalence, death, and DALYs rates of CRDs have decreased, they still cause a substantial burden and deaths worldwide. The high death and DALYs rates in low and low-middle SDI countries highlights the urgent need for improved preventive, diagnostic, and therapeutic measures. Global strategies for tobacco control, enhancing air quality, reducing occupational hazards, and fostering clean cooking fuels are crucial steps in reducing the burden of CRDs, especially in low- and lower-middle income countries.
- Publikační typ
- časopisecké články MeSH
Death receptor 6 (DR6/TNFRSF21) is a death domain-containing receptor of the TNFR superfamily with an apparent regulatory function in hematopoietic and neuronal cells. In this study we document that DR6 is an extensively posttranslationally modified transmembrane protein and that N- and O-glycosylations of amino acids in its extracellular part are mainly responsible for its approximately 40 kDa mobility shift in SDS polyacrylamide gels. Site-directed mutagenesis confirmed that all six extracellular asparagines are N-glycosylated and that the Ser/Thr/Pro cluster in the "stalk" domain juxtaposed to the cysteine-rich domains (CRDs) is a major site for the likely mucine-type of O-glycosylation. Deletion of the entire linker region between CRDs and the transmembrane domain, spanning over 130 amino acids, severely compromises the plasma membrane localization of DR6 and leads to its intracellular retention. Biosynthetic labeling with radiolabeled palmitate and side-directed mutagenesis also revealed that the membrane-proximal Cys368 in the intracellular part of DR6 is, similarly as cysteines in Fas/CD95 or DR4 ICPs, S-palmitoylated. However, palmitoylation of Cys368 is apparently not required for DR6 targeting into Brij-98 insoluble lipid rafts. In contrast, we show that N-glycosylation of the extracellular part might participate in directing DR6 into these membrane microdomains.
- MeSH
- buněčné linie MeSH
- glykosylace MeSH
- HeLa buňky MeSH
- HL-60 buňky MeSH
- Jurkat buňky MeSH
- lidé MeSH
- lipoylace MeSH
- membránové mikrodomény metabolismus MeSH
- molekulová hmotnost MeSH
- mutageneze cílená MeSH
- nádorové buněčné linie MeSH
- posttranslační úpravy proteinů MeSH
- protein - isoformy fyziologie genetika chemie MeSH
- receptory TNF genetika chemie metabolismus MeSH
- rekombinantní proteiny genetika chemie metabolismus MeSH
- sekvenční delece MeSH
- terciární struktura proteinů MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
Galectin-4, a member of the tandem-repeat subfamily of galectins, participates in cell-membrane interactions and plays an important role in cell adhesion and modulation of immunity and malignity. The oligosaccharide specificity of the mouse galectin-4 carbohydrate-recognition domains (CRDs) has been reported previously. In this work, the structure and binding properties of the N-terminal domain CRD1 were further investigated and the crystal structure of CRD1 in complex with lactose was determined at 2.1 Å resolution. The lactose-binding affinity was characterized by fluorescence measurements and two lactose-binding sites were identified: a high-affinity site with a K(d) value in the micromolar range (K(d1) = 600 ± 70 µM) and a low-affinity site with K(d2) = 28 ± 10 mM.
- MeSH
- galektin 4 chemie metabolismus MeSH
- interakční proteinové domény a motivy MeSH
- krystalografie rentgenová MeSH
- laktosa chemie metabolismus MeSH
- ligandy MeSH
- molekulární modely MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
V předložené studii se experimentálně stanovily dělící poměry diltiazemu v soustavě n-oktanolu a tlumivých roztoků o známém pH. Z těchto hodnot se vypočítaly rozdělovači koeficient a disociační konstanta diltiazemu. Léčivo s rozdělovacím koeficientem P = 597 a disociační konstantou Ka = 1,72 .10 (pKa = 7,76) bude mít předpoklady pro dobrou absorbci ve střevním traktu.
The present study experimentally determined the partition ratios of dilthiazem in the system of n-octanol and buffering solutions with known pH's. These values served to calculate the partition coefficient and dissociation constant of dilthiazem. The drug with the partition coefficient P = 597 and the dis association constant Ka = 1.72.10 (pKa=7.76) will have prerequisites for good absorption in the intestinal tract.
Galectin-4 and its homologue galectin-6 are members of the tandem-repeat subfamily of monomer divalent galectins. Expression of mouse galectin-4 and galectin-6 by RT-PCR using primers designed to distinguish both galectin transcripts indicates that both are expressed in the small intestine, colon, liver, kidney, spleen and heart and P19X1 cells while only galectin-4 is expressed in BW-5147 and 3T3 cell lines. In situ hybridization confirmed the presence of galectin-4/-6 transcripts in the liver and small intestine. Galectin-4 is expressed in spermatozoons and oocytes and its expression during early mouse emryogenesis appears in 8-cell embryos and remains in later stages, as tested by RT-PCR. To study the role of carbohydrate recognition domains (CRDs) in oligosaccharide binding and epitope recognition, we cloned mouse full-length galectin-4 and galectin-6 cDNA and constructed bacterial expression vectors producing histidin-tagged recombinant galectin-4 and its truncated CRD1 and CRD2 forms. Oligosaccharide binding profile for all recombinant forms was assessed using Glycan Array available through the Consortium for Functional Glycomics. Acquired data indicate that mGalectin-4 binds to alpha-GalNAc and alpha-Gal A and B type structures with or without fucose. While the CRD2 domain has a high specificity and affinity for A type-2 alpha-GalNAc structures, the CRD1 domain has a broader specificity in correlation to the total binding profile. These data suggest that CRD2 might be the dominant binding domain of mouse galectin-4. Mapping of epitopes reactive for biotinylated his-tagged CRD1, CRD2 and mGalectin-4 performed on mouse cryosections showed that all three forms bind to alveolar macrophages, macrophages of red pulp of the spleen and proximal tubuli of the kidney and this binding was inhibited by 5 mM lactose. Interestingly, mGalectin-4, but not CRD forms, binds to the suprabasal layer of squamous epithelium of the tongue, suggesting that the link region also plays an important role in ligand recognition.
- MeSH
- buňky 3T3 MeSH
- epitopy chemie metabolismus MeSH
- financování organizované MeSH
- galektin 4 genetika chemie MeSH
- galektiny genetika chemie MeSH
- hybridizace in situ metody MeSH
- imunohistochemie MeSH
- komplementární DNA genetika MeSH
- molekulární sekvence - údaje MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- oligosacharidy chemie metabolismus MeSH
- rekombinantní proteiny biosyntéza chemie MeSH
- sacharidové sekvence MeSH
- stanovení celkové genové exprese MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
