Protein & Cell


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In memory of Professor Tianqin Cao (Tien-chin Tsao)
Youshang Zhang,
Protein Cell    2010, 1 (6): 507-509.
Abstract   PDF (159KB)
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Human catalase: looking for complete identity
Madhur M. Goyal, Anjan Basak
Prot Cell    2010, 1 (10): 888-897.
Abstract   HTML   PDF (375KB)

Catalases are well studied enzymes that play critical roles in protecting cells against the toxic effects of hydrogen peroxide. The ubiquity of the enzyme and the availability of substrates made heme catalases the focus of many biochemical and molecular biology studies over 100 years. In human, this has been implicated in various physiological and pathological conditions. Advancement in proteomics revealed many of novel and previously unknown features of this mysterious enzyme, but some functional aspects are yet to be explained. Along with discussion on future research area, this mini-review compile the information available on the structure, function and mechanism of action of human catalase.

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Cited: Crossref(55) WebOfScience(62)
Role of helicity of α-helical antimicrobial peptides to improve specificity
Yibing Huang,Liyan He,Guirong Li,Naicui Zhai,Hongyu Jiang,Yuxin Chen
Protein Cell    2014, 5 (8): 631-642.
Abstract   PDF (438KB)

A major barrier to the use of antimicrobial peptides as antibiotics is the toxicity or ability to lyse eukaryotic cells. In this study, a 26-residue amphipathic α-helical antimicrobial peptide A12L/A20L (Ac-KWKSFLKTFKSLK KTVLHTLLKAISS-amide) was used as the framework to design a series of D- and L-diastereomeric peptides and study the relationships of helicity and biological activities of α-helical antimicrobial peptides. Peptide helicity was measured by circular dichroism spectroscopy and demonstrated to correlate with the hydrophobicity of peptides and the numbers of D-amino acid substitutions. Therapeutic index was used to evaluate the selectivity of peptides against prokaryotic cells. By introducing D-amino acids to replace the original L-amino acids on the non-polar face or the polar face of the helix, the hemolytic activity of peptide analogs have been significantly reduced. Compared to the parent peptide, the therapeutic indices were improved of 44-fold and 22-fold against Gram-negative and Grampositive bacteria, respectively. In addition, D- and L-diastereomeric peptides exhibited lower interaction with zwitterionic eukaryotic membrane and showed the significant membrane damaging effect to bacterial cells. Helicity was proved to play a crucial role on peptide specificity and biological activities. By simply replacing the hydrophobic or the hydrophilic amino acid residues on the non-polar or the polar face of these amphipathic derivatives of the parent peptide with D-amino acids, we demonstrated that this method could have excellent potential for the rational design of antimicrobial peptides with enhanced specificity.

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The next-generation sequencing technology and application
Xiaoguang Zhou, Lufeng Ren, Jun Yu, Qingshu Meng, Yuntao Li, Yude Yu,
Protein Cell    2010, 1 (6): 520-536.
Abstract   PDF (648KB)
As one of the key technologies in biomedical research, DNA sequencing has not only improved its productivity with an exponential growth rate but also been applied to new areas of application over the past few years. This is largely due to the advent of newer generations of sequencing platforms, offering ever-faster and cheaper ways to analyze sequences. In our previous review, we looked into technical characteristics of the next-generation sequencers and provided prospective insights into their future development. In this article, we present a brief overview of the advantages and shortcomings of key commercially available platforms with a focus on their suitability for a broad range of applications.
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UV-B-induced photomorphogenesis in Arabidopsis
Jigang Li, Li Yang, Dan Jin, Cynthia D. Nezames, William Terzaghi, Xing Wang Deng
Prot Cell    2013, 4 (7): 485-492.
Abstract   HTML   PDF (213KB)

Ultraviolet-B (UV-B) is a relatively minor component of sunlight, but can induce stress-related physiological processes or UV-B-specific photomorphogenic responses in plants. In the last decade, significant progress has been made in understanding the UV-B photomorphogenic pathway, including identification of the key components in the pathway, molecular characterization of UV-B photoreceptor and perception mechanism, and elucidation of the signal transduction mechanisms from the photoactivated UV-B receptor to downstream gene expression. This review summarizes the key players identified to date in the UV-B photomorphogenic pathway and their roles in mediating UV-B signal transduction.

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Animal models for the atherosclerosis research: a review
Xiangdong Li, Yuanwu Liu, Hua Zhang, Liming Ren, Qiuyan Li, Ning Li
Prot Cell    2011, 2 (3): 189-201.
Abstract   HTML   PDF (330KB)

Atherosclerosis is a leading cause of death worldwide, and its mechanisms are still unclear. However, various animal models have significantly advanced our understanding of the mechanisms involved in atherosclerosis and have allowed the evaluation of therapeutic options. The aim of this paper is to review those animal models (i.e., rabbits, mice, rats, guinea pigs, hamsters, avian, carnivores, swine, and, non-human primates) that have been used to study atherosclerosis. Though there is no single perfect animal model that completely replicates the stages of human atherosclerosis, cholesterol feeding and mechanical endothelial injury are two common features shared by most models of atherosclerosis. Further, with the development of genetically modified animals, these models are significantly broadening our understanding of the pathogenesis of atherosclerosis.

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CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes
Puping Liang,Yanwen Xu,Xiya Zhang,Chenhui Ding,Rui Huang,Zhen Zhang,Jie Lv,Xiaowei Xie,Yuxi Chen,Yujing Li,Ying Sun,Yaofu Bai,Zhou Songyang,Wenbin Ma,Canquan Zhou,Junjiu Huang
Protein Cell    2015, 6 (5): 363-372.
Abstract   PDF (1222KB)

Genome editing tools such as the clustered regularly interspaced short palindromic repeat (CRISPR)-associated system (Cas) have been widely used to modify genes in model systems including animal zygotes and human cells, and hold tremendous promise for both basic research and clinical applications. To date, a serious knowledge gap remains in our understanding of DNA repair mechanisms in human early embryos, and in the efficiency and potential off-target effects of using technologies such as CRISPR/Cas9 in human pre-implantation embryos. In this report, we used tripronuclear (3PN) zygotes to further investigate CRISPR/Cas9-mediated gene editing in human cells. We found that CRISPR/Cas9 could effectively cleave the endogenous β-globin gene (HBB). However, the efficiency of homologous recombination directed repair (HDR) of HBB was low and the edited embryos were mosaic. Off-target cleavage was also apparent in these 3PN zygotes as revealed by the T7E1 assay and whole-exome sequencing. Furthermore, the endogenous delta-globin gene (HBD), which is homologous to HBB, competed with exogenous donor oligos to act as the repair template, leading to untoward mutations. Our data also indicated that repair of the HBB locus in these embryos occurred preferentially through the non-crossover HDR pathway. Taken together, our work highlights the pressing need to further improve the fidelity and specificity of the CRISPR/Cas9 platform, a prerequisite for any clinical applications of CRSIPR/Cas9-mediated editing.

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Cryo-electron microscopy reconstructions of two types of wild rabbit hemorrhagic disease viruses characterized the structural features of Lagovirus
Zhongjun Hu, Yujia Zhai, Wei Xu, Fei Sun, Xiaojuan Tian, Dong Zheng
Protein Cell    2010, 1 (1): 48-58.
Abstract   PDF (559KB)
Rabbit hemorrhagic disease was described in China in 1984 and can cause hemorrhagic necrosis of the liver within two or three days after infection. The etiological agent, rabbit hemorrhagic disease virus (RHDV), belongs to the Lagovirus genus in the Caliciviridae family. Compared to other calicivirus, such as rNV and SMSV, the structure of Lagovirus members is not well characterized. In this report, structures of two types of wild RHDV particles, the intact virion and the core-like particle (CLP), were reconstructed by cryo-electron microscopy at 11Å and 17Å, respectively. This is the first time the 3D structure of wild caliciviruses CLP has been provided, and the 3D structure of intact RHDV virion is the highest resolution structure in Lagovirus. Comparison of the intact virion and CLP structures clearly indicated that CLP was produced from the intact virion with the protrusion dissociated. In contrast with the crystal structures of recombinant Norovirus and San Miguel sea lion virus, the capsomers of RHDV virion exhibited unique structural features and assembly modes. Both P1 and P2 subdomains have interactions inside the AB capsomer, while only P2 subdomains have interaction inside CC capsomer. The pseudo atomic models of RHDV capsomers were constructed by homology modeling and density map fitting, and the rotation of RHDV VP60 P domain with respect to its S domain, compared with SMSV, was observed. Collectively, our cryo-electron microscopic studies of RHDV provide close insight into the structure of Lagovirus, which is important for functional analysis and better vaccine development in the future.
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The role of gut microbiota in the gut-brain axis: current challenges and perspectives
Xiao Chen, Roshan D’Souza, Seong-Tshool Hong
Prot Cell    2013, 4 (6): 403-414.
Abstract   HTML   PDF (552KB)

Brain and the gastrointestinal (GI) tract are intimately connected to form a bidirectional neurohumoral communication system. The communication between gut and brain, knows as the gut-brain axis, is so well established that the functional status of gut is always related to the condition of brain. The researches on the gut-brain axis were traditionally focused on the psychological status affecting the function of the GI tract. However, recent evidences showed that gut microbiota communicates with the brain via the gut-brain axis to modulate brain development and behavioral phenotypes. These recent fi ndings on the new role of gut microbiota in the gut-brain axis implicate that gut microbiota could associate with brain functions as well as neurological diseases via the gut-brain axis. To elucidate the role of gut microbiota in the gut-brain axis, precise identification of the composition of microbes constituting gut microbiota is an essential step. However, identifi cation of microbes constituting gut microbiota has been the main technological challenge currently due to massive amount of intestinal microbes and the diffi culties in culture of gut microbes. Current methods for identifi cation of microbes constituting gut microbiota are dependent on omics analysis methods by using advanced high tech equipment. Here, we review the association of gut microbiota with the gut-brain axis, including the pros and cons of the current high throughput methods for identifi cation of microbes constituting gut microbiota to elucidate the role of gut microbiota in the gut-brain axis.

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Protein targets for structure-based anti-Mycobacterium tuberculosis drug discovery
Zhiyong Lou, Xiaoxue Zhang
Prot Cell    2010, 1 (5): 435-442.
Abstract   HTML   PDF (408KB)

Mycobacterium tuberculosis, which belongs to the genus Mycobacterium, is the pathogenic agent for most tuberculosis (TB). As TB remains one of the most rampant infectious diseases, causing morbidity and death with emergence of multi-drug-resistant and extensively-drug-resistant forms, it is urgent to identify new drugs with novel targets to ensure future therapeutic success. In this regards, the structural genomics of M. tuberculosis provides important information to identify potential targets, perform biochemical assays, determine crystal structures in complex with potential inhibitor(s), reveal the key sites/residues for biological activity, and thus validate drug targets and discover novel drugs. In this review, we will discuss the recent progress on novel targets for structure-based anti-M. tuberculosis drug discovery.

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The crosstalk between autophagy and apoptosis: where does this lead?
Claire Gordy, You-Wen He
Prot Cell    2012, 3 (1): 17-27.
Abstract   HTML   PDF (299KB)

Recent advances in the understanding of the molecular processes contributing to autophagy have provided insight into the relationship between autophagy and apoptosis. In contrast to the concept of “autophagic cell death,” accumulating evidence suggests that autophagy serves a largely cytoprotective role in physiologically relevant conditions. The cytoprotective function of autophagy is mediated in many circumstances by negative modulation of apoptosis. Apoptotic signaling, in turn, serves to inhibit autophagy. While the mechanisms mediating the complex counter-regulation of apoptosis and autophagy are not yet fully understood, important points of crosstalk include the interactions between Beclin-1 and Bcl-2/Bcl-xL and between FADD and Atg5, caspase- and calpain-mediated cleavage of autophagy-related proteins, and autophagic degradation of caspases. Continued investigation of these and other means of crosstalk between apoptosis and autophagy is necessary to elucidate the mechanisms controlling the balance between survival and death both under normal conditions and in diseases including cancer.

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Cited: Crossref(154) WebOfScience(175)
Two-dimensional gel electrophoresis in bacterial proteomics
Shirly O. T. Curreem, Rory M. Watt, Susanna K. P. Lau, Patrick C. Y. Woo
Prot Cell    2012, 3 (5): 346-363.
Abstract   HTML   PDF (487KB)

Two-dimensional gel electrophoresis (2-DE) is a gel-based technique widely used for analyzing the protein composition of biological samples. It is capable of resolving complex mixtures containing more than a thousand protein components into individual protein spots through the coupling of two orthogonal biophysical separation techniques: isoelectric focusing (first dimension) and polyacrylamide gel electrophoresis (second dimension). 2-DE is ideally suited for analyzing the entire expressed protein complement of a bacterial cell: its proteome. Its relative simplicity and good reproducibility have led to 2-DE being widely used for exploring proteomics within a wide range of environmental and medically-relevant bacteria. Here we give a broad overview of the basic principles and historical development of gel-based proteomics, and how this powerful approach can be applied for studying bacterial biology and physiology. We highlight specific 2-DE applications that can be used to analyze when, where and how much proteins are expressed. The links between proteomics, genomics and mass spectrometry are discussed. We explore how proteomics involving tandem mass spectrometry can be used to analyze (post-translational) protein modifications or to identify proteins of unknown origin by de novo peptide sequencing. The use of proteome fractionation techniques and non-gel-based proteomic approaches are also discussed. We highlight how the analysis of proteins secreted by bacterial cells (secretomes or exoproteomes) can be used to study infection processes or the immune response. This review is aimed at non-specialists who wish to gain a concise, comprehensive and contemporary overview of the nature and applications of bacterial proteomics.

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Functional annotation from the genome sequence of the giant panda
Tong Huo, Yinjie Zhang, Jianping Lin
Prot Cell    2012, 3 (8): 602-608.
Abstract   HTML   PDF (479KB)

The giant panda is one of the most critically endangered species due to the fragmentation and loss of its habitat. Studying the functions of proteins in this animal, especially specific trait-related proteins, is therefore necessary to protect the species. In this work, the functions of these proteins were investigated using the genome sequence of the giant panda. Data on 21,001 proteins and their functions were stored in the Giant Panda Protein Database, in which the proteins were divided into two groups: 20,179 proteins whose functions can be predicted by GeneScan formed the known-function group, whereas 822 proteins whose functions cannot be predicted by GeneScan comprised the unknownfunction group. For the known-function group, we further classified the proteins by molecular function, biological process, cellular component, and tissue specificity. For the unknown-function group, we developed a strategy in which the proteins were filtered by cross- Blast to identify panda-specific proteins under the assumption that proteins related to the panda-specific traits in the unknown-function group exist. After this filtering procedure, we identified 32 proteins (2 of which are membrane proteins) specific to the giant panda genome as compared against the dog and horse genomes. Based on their amino acid sequences, these 32 proteins were further analyzed by functional classification using SVM-Prot, motif prediction using MyHits, and interacting protein prediction using the Database of Interacting Proteins. Nineteen proteins were predicted to be zinc-binding proteins, thus affecting the activities of nucleic acids. The 32 panda-specific proteins will be further investigated by structural and functional analysis.

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The NLRP3 Infl ammasome activation in human or mouse cells, sensitivity causes puzzle
Hongbin Wang, Liming Mao, Guangxun Meng
Prot Cell    2013, 4 (8): 565-568.
Abstract   HTML   PDF (474KB)
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Heteromerization of TRP channel subunits: extending functional diversity
Wei Cheng, Changsen Sun, Jie Zheng
Prot Cell    2010, 1 (9): 802-810.
Abstract   HTML   PDF (312KB)

Transient receptor potential (TRP) channels are widely found throughout the animal kingdom. By serving as cellular sensors for a wide spectrum of physical and chemical stimuli, they play crucial physiological roles ranging from sensory transduction to cell cycle modulation. TRP channels are tetrameric protein complexes. While most TRP subunits can form functional homomeric channels, heteromerization of TRP channel subunits of either the same subfamily or different subfamilies has been widely observed. Heteromeric TRP channels exhibit many novel properties compared to their homomeric counterparts, indicating that co-assembly of TRP channel subunits has an important contribution to the diversity of TRP channel functions.

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Combined effects of p53 and MDM2 polymorphisms on susceptibility and surgical prognosis in hepatitis B virus-related hepatocellular carcinoma
Yun Yang, Tian Xia, Ning Li, Jin Zhang, Yuan Yang, Wenming Cong, Qiang Deng, Ke Lan, Weiping Zhou
Prot Cell    2013, 4 (1): 71-81.
Abstract   HTML   PDF (725KB)

The p53 signaling pathway works as a potent barrier to tumor progression. Two single nucleotide polymorphisms (SNPs) in the gene loci of p53 pathway, p53 codon 72 Arg72Pro and MDM2 SNP309 (T>G), have been shown to cause perturbation of p53 function, but the effect of the two SNPs on the risk of hepatocellular carcinoma (HCC) remains inconsistent. This study investigated the influence of combined p53 Arg72Pro and MDM2 SNP309 on the risk of developing HCC in patients with chronic hepatitis B virus infection, and evaluated the significance of the two combined SNPs on patient prognosis. In total, 350 HCC patients, 230 non-HCC patients, and 96 healthy controls were genotyped for the p53 Arg72Pro and MDM2 SNP309. The combined p53 Pro/Pro and MDM2 G/G genotype was significantly associated with HCC risk (P= 0.047). Multivariate analysis indicated that combined p53 Pro/Pro and MDM2 G/G genotype was an independent factor affecting recurrence and survival (P<0.05). Patients with combined p53 Pro/Pro and MDM2 G/G genotypes had a poorer prognosis than other genotypes, P<0.01 for both disease-free survival (DFS) and overall survival (OS). DFS and OS rates also differed significantly between Barcelona Clinic Liver Cancer (BCLC) stage A patients with combined p53 Pro/Pro and MDM2 G/G and other genotypes (P<0.05). Thus, the combined p53 Pro/Pro and MDM2 G/G genotype is associated with increased risk of developing HCC and is an independent adverse prognostic indicator in early stage HCC.

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NF-κB and STAT3 signaling pathways collaboratively link infl ammation to cancer
Yihui Fan, Renfang Mao, Jianhua Yang
Prot Cell    2013, 4 (3): 176-185.
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Although links between cancer and inflammation were firstly proposed in the nineteenth century, the molecular mechanism has not yet been clearly understood. Epidemiological studies have identified chronic infections and infl ammation as major risk factors for various types of cancer. NF-κB transcription factors and the signaling pathways are central coordinators in innate and adaptive immune responses. STAT3 regulates the expression of a variety of genes in response to cellular stimuli, and thus plays a key role in cell growth and apoptosis. Recently, roles of NF-κB and STAT3 in colon, gastric and liver cancers have been extensively investigated. The activation and interaction between STAT3 and NF-κB play vital roles in control of the communication between cancer cells and infl ammatory cells. NF-κB and STAT3 are two major factors controlling the ability of pre-neoplastic and malignant cells to resist apoptosis-based tumor-surveillance and regulating tumor angiogenesis and invasiveness. Understanding the molecular mechanisms of NF-κB and STAT3 cooperation in cancer will offer opportunities for the design of new chemo-preventive and chemotherapeutic approaches.

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Cited: Crossref(143) WebOfScience(160)
Chain length-dependent cooperativity in fatty acid binding and oxidation by cytochrome P450BM3 (CYP102A1)
Benjamin Rowlatt, Jake A. Yorke, Anthony J. Strong, Christopher J. C. Whitehouse, Stephen G. Bell, Luet-Lok Wong
Prot Cell    2011, 2 (8): 656-671.
Abstract   HTML   PDF (663KB)

Fatty acid binding and oxidation kinetics for wild type P450BM3 (CYP102A1) from Bacillus megaterium have been found to display chain length-dependent homotropic behavior. Laurate and 13-methyl-myristate display Michaelis-Menten behavior while there are slight deviations with myristate at low ionic strengths. Palmitate shows Michaelis-Menten kinetics and hyperbolic binding behavior in 100 mmol/L phosphate, pH 7.4, but sigmoidal kinetics (with an apparent intercept) in low ionic strength buffers and at physiological phosphate concentrations. In low ionic strength buffers both the heme domain and the full-length enzyme show complex palmitate binding behavior that indicates a minimum of four fatty acid binding sites, with high cooperativity for the binding of the fourth palmitate molecule, and the full-length enzyme showing tighter palmitate binding than the heme domain. The first flavin-to-heme electron transfer is faster for laurate, myristate and palmitate in 100 mmol/L phosphate than in 50 mmol/L Tris (pH 7.4), yet each substrate induces similar high-spin heme content. For palmitate in low phosphate buffer concentrations, the rate constant of the first electron transfer is much larger than kcat. The results suggest that phosphate has a specific effect in promoting the first electron transfer step, and that P450BM3 could modulate Bacillus membrane morphology and fluidity via palmitate oxidation in response to the external phosphate concentration.

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Horizontal transfer of microRNAs: molecular mechanisms and clinical applications
Xi Chen, Hongwei Liang, Junfeng Zhang, Ke Zen, Chen-Yu Zhang
Prot Cell    2012, 3 (1): 28-37.
Abstract   HTML   PDF (271KB)

A new class of RNA regulatory genes known as microRNAs (miRNAs) has been found to introduce a whole new layer of gene regulation in eukaryotes. The intensive studies of the past several years have demonstrated that miRNAs are not only found intracellularly, but are also detectable outside cells, including in various body fluids (e.g. serum, plasma, saliva, urine and milk). This phenomenon raises questions about the biological function of such extracellular miRNAs. Substantial amounts of extracellular miRNAs are enclosed in small membranous vesicles (e.g. exosomes, shedding vesicles and apoptotic bodies) or packaged with RNA-binding proteins (e.g. high-density lipoprotein, Argonaute 2 and nucleophosmin 1). These miRNAs may function as secreted signaling molecules to influence the recipient cell phenotypes. Furthermore, secreted extracellular miRNAs may reflect molecular changes in the cells from which they are derived and can therefore potentially serve as diagnostic indicators of disease. Several studies also point to the potential application of siRNA/miRNA delivery as a new therapeutic strategy for treating diseases. In this review, we summarize what is known about the mechanism of miRNA secretion. In addition, we describe the pathophysiological roles of secreted miRNAs and their clinical potential as diagnostic biomarkers and therapeutic drugs. We believe that miRNA transfer between cells will have a significant impact on biological research in the coming years.

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Upregulation of SIRT1 by 17β-estradiol depends on ubiquitin-proteasome degradation of PPAR-γ mediated by NEDD4-1
Limin Han, Pan Wang, Ganye Zhao, Hui Wang, Meng Wang, Jun Chen, Tanjun Tong
Prot Cell    2013, 4 (4): 310-321.
Abstract   HTML   PDF (867KB)

17β-estradiol (E2) treatment of cells results in an upregulation of SIRT1 and a down-regulation of PPARγ. The decrease in PPARγ expression is mediated by increased degradation of PPARγ. Here we report that PPARγ is ubiquitinated by HECT E3 ubiquitin ligase NEDD4-1 and degraded, along with PPARγ, in response to E2 stimulation. The PPARγ interacts with ubiquitin ligase NEDD4-1 through a conserved PPXY-WW binding motif. The WW3 domain in NEDD4-1 is critical for binding to PPARγ. NEDD4-1 overexpression leads to PPARγ ubiquitination and reduced expression of PPARγ. Conversely, knockdown of NEDD4-1 by specific siRNAs abolishes PPARγ ubiquitination. These data indicate that NEDD4-1 is the E3 ubiquitin ligase responsible for PPARγ ubiquitination. Here, we show that NEDD4-1 delays cellular senescence by degrading PPARγ expression. Taken together, our data show that E2 could upregulate SIRT1 expression via promoting the PPARγ ubiquitination-proteasome degradation pathway to delay the process of cell senescence.

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Structure and function of WD40 domain proteins
Chao Xu, Jinrong Min
Prot Cell    2011, 2 (3): 202-214.
Abstract   HTML   PDF (1126KB)

The WD40 domain exhibits a β-propeller architecture, often comprising seven blades. The WD40 domain is one of the most abundant domains and also among the top interacting domains in eukaryotic genomes. In this review, we will discuss the identification, definition and architecture of the WD40 domains. WD40 domain proteins are involved in a large variety of cellular processes, in which WD40 domains function as a protein-protein or protein-DNA interaction platform. WD40 domain mediates molecular recognition events mainly through the smaller top surface, but also through the bottom surface and sides. So far, no WD40 domain has been found to display enzymatic activity. We will also discuss the different binding modes exhibited by the large versatile family of WD40 domain proteins. In the last part of this review, we will discuss how post-translational modifications are recognized by WD40 domain proteins.

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Snapshots of a hybrid transcription factor in the Hippo pathway
Xuelian Luo
Prot Cell    2010, 1 (9): 811-819.
Abstract   HTML   PDF (528KB)

The Hippo pathway plays key roles in animal development. It suppresses tumorigenesis by controlling the transcription of the target genes that are critical for cell proliferation and apoptosis. The transcriptional coactivator YAP is the major downstream effector of the Hippo signaling. Upon extracellular stimulation, a kinase cascade in the Hippo pathway phosphorylates YAP and promotes its cytoplasmic sequestration by 14-3-3 and ubiquitin-dependent degradation. When the Hippo pathway is turned off, YAP (which lacks a DNA-binding domain) is dephosphorylated and translocates to the nucleus, where it associates with the transcription factor TEAD to form a functional heterodimeric transcription factor and to promote the expression of the Hippo-responsive genes. Recently, structures of the YAP-binding domain of TEAD alone or in complex with YAP have revealed the atomic details of the TEAD-YAP interaction. Here, I review these exciting advances, propose a strategy for targeting the TEAD-YAP interaction using small molecules, and suggest potential mechanisms by which phosphorylation and 14-3-3 binding regulate the cytoplasmic retention of YAP.

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Driving efficiency in a high-throughput metabolic stability assay through a generic high-resolution accurate mass method and automated data mining
Wenqing Shui, Song Lin, Allen Zhang, Yan Chen, Yingying Huang, Mark Sanders
Prot Cell    2011, 2 (8): 680-688.
Abstract   HTML   PDF (206KB)

Improving analytical throughput is the focus of many quantitative workflows being developed for early drug discovery. For drug candidate screening, it is common practice to use ultra-high performance liquid chromatography (U-HPLC) coupled with triple quadrupole mass spectrometry. This approach certainly results in short analytical run time; however, in assessing the true throughput, all aspects of the workflow needs to be considered, including instrument optimization and the necessity to re-run samples when information is missed. Here we describe a high-throughput metabolic stability assay with a simplified instrument set-up which significantly improves the overall assay efficiency. In addition, as the data is acquired in a non-biased manner, high information content of both the parent compound and metabolites is gathered at the same time to facilitate the decision of which compounds to proceed through the drug discovery pipeline.

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Structural and biochemical studies of RIG-I antiviral signaling
Miao Feng, Zhanyu Ding, Liang Xu, Liangliang Kong, Wenjia Wang, Shi Jiao, Zhubing Shi, Mark I. Greene, Yao Cong, Zhaocai Zhou
Prot Cell    2013, 4 (2): 142-154.
Abstract   HTML   PDF (1214KB)

Retinoic acid-inducible gene I (RIG-I) is an important pattern recognition receptor that detects viral RNA and triggers the production of type-I interferons through the downstream adaptor MAVS (also called IPS-1, CARDIF, or VISA). A series of structural studies have elaborated some of the mechanisms of dsRNA recognition and activation of RIG-I. Recent studies have proposed that K63-linked ubiquitination of, or unanchored K63-linked polyubiquitin binding to RIG-I positively regulates MAVS-mediated antiviral signaling. Conversely phosphorylation of RIG-I appears to play an inhibitory role in controlling RIG-I antiviral signal transduction. Here we performed a combined structural and biochemical study to further define the regulatory features of RIG-I signaling. ATP and dsRNA binding triggered dimerization of RIG-I with conformational rearrangements of the tandem CARD domains. Full length RIG-I appeared to form a complex with dsRNA in a 2:2 molar ratio. Compared with the previously reported crystal structures of RIG-I in inactive state, our electron microscopic structure of full length RIG-I in complex with blunt-ended dsRNA, for the first time, revealed an exposed active conformation of the CARD domains. Moreover, we found that purified recombinant RIG-I proteins could bind to the CARD domain of MAVS independently of dsRNA, while S8E and T170E phosphorylation-mimicking mutants of RIG-I were defective in binding E3 ligase TRIM25, unanchored K63-linked polyubiquitin, and MAVS regardless of dsRNA. These findings suggested that phosphorylation of RIG inhibited downstream signaling by impairing RIG-I binding with polyubiquitin and its interaction with MAVS.

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Mitochondrial calcium uniporter protein MCU is involved in oxidative stress-induced cell death
Yajin Liao,Yumin Hao,Hong Chen,Qing He,Zengqiang Yuan,Jinbo Cheng
Protein Cell    2015, 6 (6): 434-442.
Abstract   PDF (1273KB)

Mitochondrial calcium uniporter (MCU) is a conserved Ca2+ transporter at mitochondrial in eukaryotic cells. However, the role of MCU protein in oxidative stressinduced cell death remains unclear. Here, we showed that ectopically expressed MCU is mitochondrial localized in both HeLa and primary cerebellar granule neurons (CGNs). Knockdown of endogenous MCU decreases mitochondrial Ca2+ uptake following histamine stimulation and attenuates cell death induced by oxidative stress in both HeLa cells and CGNs. We also found MCU interacts with VDAC1 and mediates VDAC1 overexpression-induced cell death in CGNs. This finding demonstrates that MCU-VDAC1 complex regulates mitochondrial Ca2+ uptake and oxidative stress-induced apoptosis, which might represent therapeutic targets for oxidative stress related diseases.

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To be EndMT or not to be, that is the question in pulmonary hypertension
Jianhua Xiong
Protein Cell    2015, 6 (8): 547-550.
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Thyroid hormone action in metabolic regulation
Yiyun Song, Xuan Yao, Hao Ying
Prot Cell    2011, 2 (5): 358-368.
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Thyroid hormone plays pivotal roles in growth, differentiation, development and metabolic homeostasis via thyroid hormone receptors (TRs) by controlling the expression of TR target genes. The transcriptional activity of TRs is modulated by multiple factors including various TR isoforms, diverse thyroid hormone response elements, different heterodimeric partners, coregulators, and the cellular location of TRs. In the present review, we summarize recent advance in understanding the molecular mechanisms of thyroid hormone action obtained from human subject research, thyroid hormone mimetics application, TR isoform-specific knock-in mouse models, and mitochondrion study with highlights in metabolic regulations. Finally, as future perspectives, we share our thoughts about current challenges and possible approaches to promote our knowledge of thyroid hormone action in metabolism.

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Structural basis of heparan sulfate-specific degradation by heparinase III
Wei Dong, Weiqin Lu, Wallace L. McKeehan, Yongde Luo, Sheng Ye
Prot Cell    2012, 3 (12): 950-961.
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Heparinase III (HepIII) is a 73-kDa polysaccharide lyase (PL) that degrades the heparan sulfate (HS) polysaccharides at sulfate-rare regions, which are important co-factors for a vast array of functional distinct proteins including the well-characterized antithrombin and the FGF/FGFR signal transduction system. It functions in cleaving metazoan heparan sulfate (HS) and providing carbon, nitrogen and sulfate sources for host microorganisms. It has long been used to deduce the structure of HS and heparin motifs; however, the structure of its own is unknown. Here we report the crystal structure of the HepIII from Bacteroides thetaiotaomicron at a resolution of 1.6 ?. The overall architecture of HepIII belongs to the (α/α)5 toroid subclass with an N-terminal toroid-like domain and a C-terminal β-sandwich domain. Analysis of this high-resolution structure allows us to identify a potential HS substrate binding site in a tunnel between the two domains. A tetrasaccharide substrate bound model suggests an elimination mechanism in the HS degradation. Asn260 and His464 neutralize the carboxylic group, whereas Tyr314 serves both as a general base in C-5 proton abstraction, and a general acid in a proton donation to reconstitute the terminal hydroxyl group, respectively. The structure of HepIII and the proposed reaction model provide a molecular basis for its potential practical utilization and the mechanism of its eliminative degradation for HS polysaccarides.

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Role of plant autophagy in stress response
Shaojie Han, Bingjie Yu, Yan Wang, Yule Liu
Prot Cell    2011, 2 (10): 784-791.
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Autophagy is a conserved pathway for the bulk degradation of cytoplasmic components in all eukaryotes. This process plays a critical role in the adaptation of plants to drastic changing environmental stresses such as starvation, oxidative stress, drought, salt, and pathogen invasion. This paper summarizes the current knowledge about the mechanism and roles of plant autophagy in various plant stress responses.

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A novel xeno-free and feeder-cell-free system for human pluripotent stem cell culture
Qihui Wang, Xiaoning Mou, Henghua Cao, Qingzhang Meng, Yanni Ma, Pengcheng Han, Junjie Jiang, Hao Zhang, Yue Ma
Prot Cell    2012, 3 (1): 51-59.
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While human induced pluripotent stem cells (hiPSCs) have promising applications in regenerative medicine, most of the hiPSC lines available today are not suitable for clinical applications due to contamination with non-human materials, such as sialic acid, and potential pathogens from animal-product-containing cell culture systems. Although several xeno-free cell culture systems have been established recently, their use of human fibroblasts as feeders reduces the clinical potential of hiPSCs due to batch-to-batch variation in the feeders and time-consuming preparation processes. In this study, we have developed a xeno-free and feeder-cell-free human embryonic stem cell (hESC)/hiPSC culture system using human plasma and human placenta extracts. The system maintains the self-renewing capacity and pluripotency of hESCs for more than 40 passages. Human iPSCs were also derived from human dermal fibroblasts using this culture system by overexpressing three transcription factors—Oct4, Sox2 and Nanog. The culture system developed here is inexpensive and suitable for large scale production.

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