38 research outputs found

    Structural insights into the similar modes of Nrf2 transcription factor recognition by the cytoplasmic repressor Keap1

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    The structure of mouse Keap1-DC complexed with the DLG motif peptide of Nrf2 transcription factor was determined at 1.9 Å resolution. The structure showed that the peptide binds to Keap1-DC at the bottom region of the β-propeller domain

    Solution Structure of a TBP–TAFII230 Complex Protein Mimicry of the Minor Groove Surface of the TATA Box Unwound by TBP

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    AbstractGeneral transcription factor TFIID consists of TATA box–binding protein (TBP) and TBP-associated factors (TAFIIs), which together play a central role in both positive and negative regulation of transcription. The N-terminal region of the 230 kDa Drosophila TAFII (dTAFII230) binds directly to TBP and inhibits TBP binding to the TATA box. We report here the solution structure of the complex formed by dTAFII230 N-terminal region (residues 11–77) and TBP. dTAFII23011–77 comprises three α helices and a β hairpin, forming a core that occupies the concave DNA-binding surface of TBP. The TBP-binding surface of dTAFII230 markedly resembles the minor groove surface of the partially unwound TATA box in the TBP–TATA complex. This protein mimicry of the TATA element surface provides the structural basis of the mechanism by which dTAFII230 negatively controls the TATA box–binding activity within the TFIID complex

    Peroxisome division in the yeast Yarrowia lipolytica is regulated by a signal from inside the peroxisome

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    We describe an unusual mechanism for organelle division. In the yeast Yarrowia lipolytica, only mature peroxisomes contain the complete set of matrix proteins. These mature peroxisomes assemble from several immature peroxisomal vesicles in a multistep pathway. The stepwise import of distinct subsets of matrix proteins into different immature intermediates along the pathway causes the redistribution of a peroxisomal protein, acyl-CoA oxidase (Aox), from the matrix to the membrane. A significant redistribution of Aox occurs only in mature peroxisomes. Inside mature peroxisomes, the membrane-bound pool of Aox interacts with Pex16p, a membrane-associated protein that negatively regulates the division of early intermediates in the pathway. This interaction inhibits the negative action of Pex16p, thereby allowing mature peroxisomes to divide

    Human general transcription factor TFIIB: conformational variability and interaction with VP16 activation domain

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    ABSTRACT: Human TFIIB, an essential factor in transcription of protein-coding genes by RNA polymerase II, consists of an amino-terminal zinc binding domain (TFIIBn) connected by a linker of about 60 residues to a carboxy-terminal core domain (TFIIBc). The TFIIB core domain has two internally repeated motifs, each comprising five R-helices arranged as in the cyclin box. Compared to the crystal structure of TFIIBc in complex with TBP and a TATA-containing oligonucleotide, the NMR-derived solution structure of free TFIIBc is more compact, with a different repeat-repeat orientation and a significantly shorter first helix in the second repeat. Analysis of backbone 15 N relaxation parameters indicates the presence of relatively large amplitude, nanosecond time-scale motions in the TFIIBc interrepeat linker and structural fluctuations throughout the backbone. Interaction of TFIIBc with the acidic activation domain of VP16 or with TFIIBn induces 1 H-15 N chemical shift and line width changes concentrated in the first repeat, interrepeat linker and the first helix of the second repeat. These results suggest that TFIIB is somewhat pliable and that the conformation of the C-terminal core domain can be modulated by interaction with the N-terminal zinc binding domain. Furthermore, binding of the VP16 activation domain may promote TFIIBc conformations primed for binding to a TBP-DNA complex. TFIIB is an essential factor for initiation of transcription of protein-coding genes by RNA polymerase II (RNAPII), 1 one of the three eukaryotic nuclear RNA polymerases. Each of these polymerases requires a distinct set of auxiliary protein factors for specific initiation of RNA synthesis. In addition to TFIIB, the general initiation factors for RNAPII are TFIIA, TFIID [TATA binding protein (TBP) is a subunit of TFIID], TFIIE, TFIIF, and TFIIH (1-4). In the stepwise model for assembly of a transcription preinitiation complex (PIC) (1-3), TFIIB binds to the TBP (TFIID)-DNA complex and acts as a molecular bridge to RNAPII and the remaining initiation factors (5). TFIIB possesses sequencespecific DNA binding capacity for a DNA segment termed the IIB recognition element (BRE) immediately upstream of the TATA sequence of the adenovirus major late promoter Human TFIIB is a 316-residue polypeptid

    Histone Demethylase JMJD2B Functions as a Co-Factor of Estrogen Receptor in Breast Cancer Proliferation and Mammary Gland Development

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    Estrogen is a key regulator of normal function of female reproductive system and plays a pivotal role in the development and progression of breast cancer. Here, we demonstrate that JMJD2B (also known as KDM4B) constitutes a key component of the estrogen signaling pathway. JMJD2B is expressed in a high proportion of human breast tumors, and that expression levels significantly correlate with estrogen receptor (ER) positivity. In addition, 17-beta-estradiol (E2) induces JMJD2B expression in an ERα dependent manner. JMJD2B interacts with ERα and components of the SWI/SNF-B chromatin remodeling complex. JMJD2B is recruited to ERα target sites, demethylates H3K9me3 and facilitates transcription of ER responsive genes including MYB, MYC and CCND1. As a consequence, knockdown of JMJD2B severely impairs estrogen-induced cell proliferation and the tumor formation capacity of breast cancer cells. Furthermore, Jmjd2b-deletion in mammary epithelial cells exhibits delayed mammary gland development in female mice. Taken together, these findings suggest an essential role for JMJD2B in the estrogen signaling, and identify JMJD2B as a potential therapeutic target in breast cancer

    Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

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    Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

    Solution structure of the c-terminal core domain of human TFIIB: Similarity to cyclin A and interaction with TATA-binding protein

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    Abstract TFIIB is an essential component of the machinery that transcribes protein-coding genes. The three-dimensional structure of the human TFIIB core domain (TFIIB c ) has been determined using multidimensional heteronuclear magnetic resonance spectroscopy. The molecule consists of two direct repeats that adopt similar α-helical folds, conferring pseudo-twofold symmetry. An extensive, central basic surface including an amphipathic a helix is critical to the function of TFIIB as a bridge between the TBP-promoter complex and RNA polymerase II and associated general and regulatory transcription factors. Similarities between the TFIIB c and cyclin A folds indicate that elements of the eukaryotic cell cycle control apparatus evolved from more fundamental transcriptional control components, demonstrating a link between the transcription and cell cycle molecular machineries
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