TDP-43 is a pathogenic protein: its normal function in binding to UG-rich RNA is related to cystic fibrosis, and inclusion of its C-terminal fragments in brain cells is directly linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here we report the 1.65 Å crystal structure of the C-terminal RRM2 domain of TDP-43 in complex with a single-stranded DNA. We show that TDP-43 is a dimeric protein with two RRM domains, both involved in DNA and RNA binding. The crystal structure reveals the basis of TDP-43's TG/UG preference in nucleic acids binding. It also reveals that RRM2 domain has an atypical RRM-fold with an additional β-strand involved in making protein–protein interactions. This self association of RRM2 domains produced thermal-stable RRM2 assemblies with a melting point greater than 85°C as monitored by circular dichroism at physiological conditions. These studies thus characterize the recognition between TDP-43 and nucleic acids and the mode of RRM2 self association, and provide molecular models for understanding the role of TDP-43 in cystic fibrosis and the neurodegenerative diseases related to TDP-43 proteinopathy.
It is difficult to accurately estimate species richness if there are many almost undetectable species in a hyper-diverse community. Practically, an accurate lower bound for species richness is preferable to an inaccurate point estimator. The traditional nonparametric lower bound developed by Chao (1984, Scandinavian Journal of Statistics 11, 265-270) for individual-based abundance data uses only the information on the rarest species (the numbers of singletons and doubletons) to estimate the number of undetected species in samples. Applying a modified Good-Turing frequency formula, we derive an approximate formula for the first-order bias of this traditional lower bound. The approximate bias is estimated by using additional information (namely, the numbers of tripletons and quadrupletons). This approximate bias can be corrected, and an improved lower bound is thus obtained. The proposed lower bound is nonparametric in the sense that it is universally valid for any species abundance distribution. A similar type of improved lower bound can be derived for incidence data. We test our proposed lower bounds on simulated data sets generated from various species abundance models. Simulation results show that the proposed lower bounds always reduce bias over the traditional lower bounds and improve accuracy (as measured by mean squared error) when the heterogeneity of species abundances is relatively high. We also apply the proposed new lower bounds to real data for illustration and for comparisons with previously developed estimators.
We previous reported that Sp1 recruits c-Jun to the promoter of the 12(S)-lipoxygenase gene in 12-myristate 13-acetate-treated cells. We now show that Sp1 that recruited HDAC1 to the Sp1/cJun complex was constitutively acetylated when cells were exposed to phorbol 12-myristate 13-acetate (PMA) (3 h). Prolonged stimulation of the cells with PMA (9 h), however, caused the dissociation of histone deacetylase 1 (HDAC1) and the deacetylation of Sp1, with the latter being able to recruit p300 that in turn caused the acetylation and dissociation of histone 3, thus enhancing the expression of 12(S)-lipoxygenase. We also overexpressed an Sp1 mutant (K703/A, lacking acetylation sites) in the cell and found that cells recruited more p300 and expressed more 12(S)-lipoxygenase. Taken together, our results indicated that Sp1 recruits HDAC1 together with c-Jun to the gene promoter, followed by deacetylation of Sp1 upon PMA treatment. p300 is then recruited to the gene promoter through the interaction with deacetylated Sp1 to acetylate histone 3, leading to the enhancement of the expression of 12(S)-lipoxygenase.
Background: TDP-43 forms aggregates in various neurodegenerative disorders.Results: The C-terminal-truncated RRM2 of TDP-43 forms non-amyloid fibrils in vitro and plays a dominant role in forming inclusions in vivo.Conclusion: The proteolytic cleavage of TDP-43 that removes the N-terminal dimerization domain may produce unassembled truncated RRM2 fragments for aggregation.Significance: This result provides a new direction for the prevention and treatment of TDP-43-associated diseases.
Our ability to model the dynamics of signal transduction networks will depend on accurate methods to quantify levels of protein phosphorylation on a global scale. Here we describe a motif-targeting quantitation method for phosphorylation stoichiometry typing. Proteome-wide phosphorylation stoichiometry can be obtained by a simple phosphoproteomic workflow integrating dephosphorylation and isotope tagging with enzymatic kinase reaction. Proof-of-concept experiments using CK2-, MAPK- and EGFR-targeting assays in lung cancer cells demonstrate the advantage of kinase-targeted complexity reduction, resulting in deeper phosphoproteome quantification. We measure the phosphorylation stoichiometry of >1,000 phosphorylation sites including 366 low-abundance tyrosine phosphorylation sites, with high reproducibility and using small sample sizes. Comparing drug-resistant and sensitive lung cancer cells, we reveal that post-translational phosphorylation changes are significantly more dramatic than those at the protein and messenger RNA levels, and suggest potential drug targets within the kinase–substrate network associated with acquired drug resistance.
The transcription factor Sp1 is ubiquitously expressed in different cells and thereby regulates the expression of genes involved in many cellular processes. This study reveals that Sp1 was phosphorylated during the mitotic stage in three epithelial tumor cell lines and one glioma cell line. By using different kinase inhibitors, we found that during mitosis in HeLa cells, the c-Jun NH 2 -terminal kinase (JNK) 1 was activated that was then required for the phosphorylation of Sp1. In addition, blockade of the Sp1 phosphorylation via inhibition JNK1 activity in mitosis resulted in the ubiquitination and degradation of Sp1. JNK1 phosphorylated Sp1 at Thr278/739. The Sp1 mutated at Thr278/739 was unstable during mitosis, possessing less transcriptional activity for the 12(S)-lipoxygenase expression and exhibiting a decreased cell growth rate compared with wild-type Sp1 in HeLa cells. In N-methyl-N-nitrosourea-induced mammary tumors, JNK1 activation provided a potential relevance with the accumulation of Sp1. Together, our results indicate that JNK1 activation is necessary to phosphorylate Sp1 and to shield Sp1 from the ubiquitin-dependent degradation pathway during mitosis in tumor cell lines. INTRODUCTIONThe transcription factor Sp1 is ubiquitously expressed in mammalian cells, and it is important in a variety of physiological processes, including cell cycle regulation, apoptosis, and differentiation (Firestone and Bjeldanes, 2003;Chu and Ferro, 2005;Wong et al., 2005;Deniaud et al., 2006). Sp1 binds specifically to the GC-rich promoter elements, via three C 2 H 2 -type zinc finger regions at the C terminus of Sp1, and it regulates the transcriptional activity of the target genes by using two major glutamine-rich transactivation domains localized, respectively, at the N terminus and the medial region (Suske, 1999;Bouwman and Philipsen, 2002). In addition, in Sp1, there are serine/threonine-rich sequences between the two transactivation domains that may be a target for posttranslational modification (Bouwman and Philipsen, 2002).The transcriptional activity of a transcription factor is determined at least by three factors: transactivational activity, DNA binding affinity, and protein level. Previous studies on the regulation of Sp1 activities focused mostly on transactivational activity, thereby allowing study of its interaction with other proteins and its DNA binding affinity. However, one of the apparent key elements regulating the activity of Sp1 is via its stability, which certainly needs to be explored and established. Recent studies revealed that the DNA binding ability, transactivational activity, and protein stability of Sp1 might be influenced by its posttranslational modifications such as sumoylation, glycosylation, ubiquitination, acetylation, and phosphorylation (Han and Kudlow, 1997;Mortensen et al., 1997;Wells et al., 2001;Ryu et al., 2003;Abdelrahim and Safe, 2005;Chu and Ferro, 2005;Hung et al., 2006;Spengler and Brattain, 2006). For example, Sp1 is sumoylated at Lys16, which might repress the transact...
Varieties of Democracy (V-Dem) is a new approach to the conceptualization and measurement of democracy. It is co-hosted by the University of Gothenburg and University of Notre Dame. With a V-Dem Institute at University of Gothenburg that comprises almost ten staff members, and a project team across the world with four Principal Investigators, fifteen Project Managers, 30+ Regional Managers, 170 Country Coordinators, Research Assistants, and 2,500 Country Experts, the V-Dem project is one of the largest-ever social science research-oriented data collection programs.Please address comments and/or queries for information to: AbstractThe V-Dem index on women's political empowerment provides information about women's civil liberties, civil society participation, and political participation globally. Spanning from 1900 to 2012, three dimensions of empowerment, and over 170 countries, it is among the most comprehensive measures of women's empowerment available. This paper presents a conceptualization of women's political empowerment and provides an overview of the construction of the index and operationalization of its three sub-dimensions: Women's civil liberties, civil society participation, and political participation. Compared to other indices measuring women's empowerment, such as the GDI, the GEM, the GII and the CIRI data on human rights, the V-Dem index allows more precise measurement and is superior in temporal scope and coverage of countries of the Global South. The paper demonstrates the benefits of this new index and its sub-dimensions through several empirical illustrations.3
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