分类： 生物学 >> 生物物理学 分类： 化学 >> 物理化学 分类： 生物学 >> 生物物理学 提交时间： 2024-04-16
摘要： Transcription factor (TF) are proteins that regulates the transcription of genetic information from DNA to messenger RNA by binding to a specific DNA sequence.Nucleic acid-protein interactions are crucial in regulating transcription in biological systems. This work presents a quick and convenient method for constructing tight-binding models and offers physical insights into the electronic structure properties of transcription factor complexes and DNA motifs. The tight binding Hamiltonian parameters are generated using the random forest regression algorithm, which reproduces the given ab-initiolevel calculations with reasonable accuracy. We present a library of residue-level parameters derived from extensive electronic structure calculations over various possible combinations of nucleobases and amino acid side chains from high-quality DNA-protein complex structures. As an example, our approach can reasonably generate the subtle electronic structure details for the orthologous transcription factors human AP-1 and Epstein-Barr virus Zta within a few seconds on a laptop. This method potentially enhances our understanding of the electronic structure variationsof gene-protein interaction complexes, even those involving dozens of proteins and genes. We hope this study offers a powerful tool for analyzing transcription regulation mechanisms at an electronic structural level.
分类： 生物学 >> 生物物理学 >> 细胞生物学 提交时间： 2016-05-12
Cao, Duanfang
Wang, Mingzhu
Yang, Na
Xu, Rui-Ming
Cao, Duanfang
Xu, Rui-Ming
Qiu, Xiayang
Liu, Dongxiang
Jiang, Hualiang
摘要： Sirtuins with an extended N-terminal domain (NTD), represented by yeast Sir2 and human SIRT1, harbor intrinsic mechanisms for regulation of their NAD-dependent deacetylase activities. Elucidation of the regulatory mechanisms is crucial for understanding the biological functions of sirtuins and development of potential therapeutics. In particular, SIRT1 has emerged as an attractive therapeutic target, and the search for SIRT1-activating compounds (STACs) has been actively pursued. However, the effectiveness of a class of reported STACs (represented by resveratrol) as direct SIRT1 activators is under debate due to the complication involving the use of fluorogenic substrates in in vitro assays. Future efforts of SIRT1-based therapeutics necessitate the dissection of the molecular mechanism of SIRT1 stimulation. We solved the structure of SIRT1 in complex with resveratrol and a 7-amino-4-methylcoumarin (AMC)-containing peptide. The structure reveals the presence of three resveratrol molecules, two of which mediate the interaction between the AMC peptide and the NTD of SIRT1. The two NTD-bound resveratrol molecules are principally responsible for promoting tighter binding between SIRT1 and the peptide and the stimulation of SIRT1 activity. The structural information provides valuable insights into regulation of SIRT1 activity and should benefit the development of authentic SIRT1 activators.
分类： 生物学 >> 生物物理学 >> 免疫学 提交时间： 2016-05-12
摘要： Neutrophils express Toll-like receptors (TLRs) for the recognition of conserved bacterial elements to initiate antimicrobial responses. However, whether other cytosolic DNA sensors are expressed by neutrophils remains elusive. Here we found constitutive expression of the transcription factor Sox2 in the cytoplasm of mouse and human neutrophils. Neutrophil-specific Sox2 deficiency exacerbated bacterial infection. Sox2 directly recognized microbial DNA through its high-mobility-group (HMG) domain. Upon challenge with bacterial DNA, Sox2 dimerization was needed to activate a complex of the kinase TAK1 and its binding partner TAB2, which led to activation of the transcription factors NE-kappa B and AP-1 in neutrophils. Deficiency in TAK1 or TAB2 impaired Sox2-mediated antibacterial immunity. Overall, we reveal a previously unrecognized role for Sox2 as a cytosolic sequence-specific DNA sensor in neutrophils, which might provide potential therapeutic strategies for the treatment of infectious diseases.
分类： 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学 提交时间： 2016-05-11
Liu, Lian
Zhang, Shao-Wu
Zhang, Yu-Chen
Chen, Runsheng
Liu, Hui
Zhang, Lin
Chen, Runsheng
Huang, Yufei
Meng, Jia
摘要： Biochemical modifications to mRNA, especially N6-methyladenosine (m(6)A) and 5-methylcytosine (m(5)C), have been recently shown to be associated with crucial biological functions. Despite the intriguing advancements, little is known so far about the dynamic landscape of RNA methylome across different cell types and how the epitranscriptome is regulated at the system level by enzymes, i.e., RNA methyltransferases and demethylases. To investigate this issue, a meta-analysis of m(6)A MeRIP-Seq datasets collected from 10 different experimental conditions (cell type/tissue or treatment) is performed, and the combinatorial epitranscriptome, which consists of 42758 m(6)A sites, is extracted and divided into 3 clusters, in which the methylation sites are likely to be hyper- or hypo-methylated simultaneously (or co-methylated), indicating the sharing of a common methylation regulator. Four different clustering approaches are used, including K-means, hierarchical clustering (HC), Bayesian factor regression model (BFRM) and nonnegative matrix factorization (NMF) to unveil the co-methylation patterns. To validate whether the patterns are corresponding to enzymatic regulators, i.e., RNA methyltransferases or demethylases, the target sites of a known m(6)A regulator, fat mass and obesity-associated protein (FTO), are identified from an independent mouse MeRIP-Seq dataset and lifted to human. Our study shows that 3 out of the 4 clustering approaches used can successfully identify a group of methylation sites overlapping with FTO target sites at a significance level of 0.05 (after multiple hypothesis adjustment), among which, the result of NMF is the most significant (p-value 2.81 x 10(-06)). We defined a new approach evaluating the consistency between two clustering results which shows that clustering results of different methods are highly correlated strongly indicating the existence of co-methylation patterns. Consistent with recent studies, a number of cancer and neuronal disease-related bimolecular functions are enriched in the identified clusters, which are biological functions that can be regulated at the epitranscriptional level, indicating the pharmaceutical prospect of RNA N6-methyladenosine-related studies. This result successfully reveals the linkage between the global RNA co-methylation patterns embedded in the epitranscriptomic data under multiple experimental conditions and the latent enzymatic regulators, suggesting a promising direction towards a more comprehensive understanding of the epitranscriptome.
分类： 生物学 >> 生物物理学 >> 衰老生物学 提交时间： 2016-05-11
Wang, Xiumei
He, Rongqiao
Liu, Ying
Lupo, Giuseppe
Harris, William A.
Lupo, Giuseppe
Barsacchi, Giuseppina
摘要： Background: Hedgehog (Hh) signals are instrumental to the dorsoventral patterning of the vertebrate eye, promoting optic stalk and ventral retinal fates and repressing dorsal retinal identity. There has been limited analysis, however, of the critical window during which Hh molecules control eye polarity and of the temporal changes in the responsiveness of eye cells to these signals. Results: In this study, we used pharmacological and molecular tools to perform stage-specific manipulations of Hh signalling in the developing Xenopus eye. In gain-of-function experiments, most of the eye was sensitive to ventralization when the Hh pathway was activated starting from gastrula/neurula stages. During optic vesicle stages, the dorsal eye became resistant to Hh-dependent ventralization, but this pathway could partially upregulate optic stalk markers within the retina. In loss-of-function assays, inhibition of Hh signalling starting from neurula stages caused expansion of the dorsal retina at the expense of the ventral retina and the optic stalk, while the effects of Hh inhibition during optic vesicle stages were limited to the reduction of optic stalk size. Conclusions: Our results suggest the existence of two competence windows during which the Hh pathway differentially controls patterning of the eye region. In the first window, between the neural plate and the optic vesicle stages, Hh signalling exerts a global influence on eye dorsoventral polarity, contributing to the specification of optic stalk, ventral retina and dorsal retinal domains. In the second window, between optic vesicle and optic cup stages, this pathway plays a more limited role in the maintenance of the optic stalk domain. We speculate that this temporal regulation is important to coordinate dorsoventral patterning with morphogenesis and differentiation processes during eye development.
分类： 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学 提交时间： 2016-05-11
Wang, Zai
You, Jia
Xu, Shiqing
Zhang, Wenjian
Deng, Tingting
Fang, Qing
Liu, Honglin
Peng, Liang
Lou, Jinning
Hua, Zhan
Fang, Ni
Wang, Peigang
摘要： A significant portion of human and rat insulinomas coexpress multiple hormones. This character termed as multihormonality is also observed in some early pancreatic endocrine cells which coexpress insulin and glucagon, suggesting an incomplete differentiation status of both cells. Here we demonstrate that insulinoma cells INS-1 and INS-1-derived single cell clone INS-1-15 coexpressed insulin and glucagon in a portion of cells. These two hormones highly colocalized in the intracellular vesicles within a cell. Due to the existence of both PC1/3 and PC2 in INS-1-derived cells, proglucagon could be processed into glucagon, GLP-1 and GLP-2. These glucagon-family peptides and insulin were secreted simultaneously corresponding to the elevating glucose concentrations. The coexpression and partial colocalization of insulin and glucagon was also observed in rat fetal pancreatic endocrine cells, but the colocalization rate was generally lower and more diverse, suggesting that in the developing pancreatic endocrine cells, insulin and glucagon may be stored in nonidentical pools of secreting vesicles and might be secreted discordantly upon stimulus. (C) 2015 Elsevier Inc. All rights reserved.
分类： 生物学 >> 植物学 >> 植物生理学 提交时间： 2016-05-04
摘要： The great need for more sustainable alternatives to fossil fuels has increased our research interests in algal biofuels. Microalgal cells, characterized by high photosynthetic efficiency and rapid cell division, are an excellent source of neutral lipids as potential fuel stocks. Various stress factors, especially nutrient-starvation conditions, induce an increased formation of lipid bodies filled with triacylglycerol in these cells. Here we review our knowledge base on glycerolipid synthesis in the green algae with an emphasis on recent studies on carbon flux, redistribution of lipids under nutrient-limiting conditions and its regulation. We discuss the contributions and limitations of classical and novel approaches used to elucidate the algal triacylglycerol biosynthetic pathway and its regulatory network in green algae. Also discussed are gaps in knowledge and suggestions for much needed research both on the biology of triacylglycerol accumulation and possible avenues to engineer improved algal strains.
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