The WD40 domain exhibits aβ-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 ...The WD40 domain exhibits aβ-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.展开更多
目的运用网络药理学分析方法进行仙灵骨葆治疗骨质疏松症(osteoporosis,OP)的药理机制分析。方法借助中药系统药理学数据库和分析平台以及中药综合数据库获取仙灵骨葆活性成分以及相关靶标,运用Cytoscape 3.7.1软件绘制“活性成分-靶标...目的运用网络药理学分析方法进行仙灵骨葆治疗骨质疏松症(osteoporosis,OP)的药理机制分析。方法借助中药系统药理学数据库和分析平台以及中药综合数据库获取仙灵骨葆活性成分以及相关靶标,运用Cytoscape 3.7.1软件绘制“活性成分-靶标”网络图,以“osteoporosis”为关键词从GeneCards:The Human Gene Database获取OP相关基因,运用STRING数据分析平台进行PPI(protein-protein interaction)网络分析,运用DAVID数据分析平台进行基因本体(gene ontology,GO)生物过程富集以及京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析,并运用Cytoscape 3.7.1软件绘制“通路-靶标”网络图。结果共获取仙灵骨葆相关活性成分115种,核心活性成分有槲皮素、山奈酚、木犀草素、淫羊藿苷元、丹参酮IIA等。活性成分所涉及的靶标共有301个,核心靶标有PTGS2、PTGS1、ESR1等。PPI网络显示了111种核心蛋白之间的互作关系,主要与调节细胞周期有关。GO富集生物过程经筛选后共获得46项,所得生物过程亦与细胞周期有关,正调控NF-kappaB转录活性因子的过程是OP发生的机制之一,与现有研究符合。KEGG通路富集共获得37项,提示仙灵骨葆治疗OP作用集中于PI3K-Akt、TNF、MAPK、Estrogen等信号通路。结论仙灵骨葆核心活性成分中,黄酮类化合物主要通过调节OPG/RANK/RANKL,抑制破骨细胞,促进成骨细胞分化;淫羊藿苷元可增强成骨细胞活性。核心靶标PTGS2可限制M-CSF以及RANKL的表达,进而影响成骨/破骨细胞分化;雌激素受体与绝经后骨质疏松密切相关。核心通路如PI3K-Akt信号通路可增加骨量、促进成骨细胞分化;TNF信号通路、MAPK信号通路等均与成骨细胞分化有关;雌激素信号通路以及GnRh信号通路为仙灵骨葆干预绝经后骨质疏松提供依据。因此仙灵骨葆干预OP机制是通过多种途径、多种靶标、多种信号通路同时�展开更多
Ethylene insensitive 2 （EIN2）, an integral membrane protein of the ER network, has been identified as the central regulator of the ethylene signaling pathway. Still, the mechanism by which the ethylene signal is tra...Ethylene insensitive 2 （EIN2）, an integral membrane protein of the ER network, has been identified as the central regulator of the ethylene signaling pathway. Still, the mechanism by which the ethylene signal is transferred from the receptors to EIN2 has not been solved yet. Here, we show that protein phosphorylation is a key mechanism to control the interaction of EIN2 and the receptors. In vivo and in vitro fluorescence studies reveal that the kinase domain of the receptors is essential for the interaction. Cyanide, an ethylene agonist, which is known to reduce auto-phosphorylation of the ethylene receptor ethylene resistant 1 （ETR1） or a mutation in the kinase domain of ETR1 that prevents autophosphorylation （H353A）, increases the affinity of the receptors for EIN2. On the other hand, mimicking permanent auto-phosphorylation of ETR1 as in the mutant H353E releases the EiN2-ETR1 interaction from the control by the plant hormone. Based on our data, we propose a novel model on the integration of EIN2 in the ethylene signaling cascade.展开更多
In complex, constantly changing environments, plants have developed astonishing survival strategies. These elaborated strategies rely on rapid and precise gene regulation mediated by transcription factors （TFs）. TFs...In complex, constantly changing environments, plants have developed astonishing survival strategies. These elaborated strategies rely on rapid and precise gene regulation mediated by transcription factors （TFs）. TFs represent a large fraction of plant genomes and among them, MYBs and basic helix-loop-helix （bHLHs） have unique inherent properties specific to plants. Proteins of these two TF families can act as homo- or heterodimers, associate with proteins from other protein families, or form MYB/bHLH complexes to regulate distinct cellular processes. The ability of MYBs and bHLHs to interact with multiple protein part- ners has evolved to keep up with the increased metabolic complexity of multi-cellular organisms. Associ- ation and disassociation of dynamic TF complexes in response to developmental and environmental cues are controlled through a plethora of regulatory mechanisms specifically modulating TF activity. Regulation of TFs at the protein level is critical for efficient and precise control of their activity, and thus provides the mechanistic basis for a rapid on-and-off switch of TF activity. In this review, examples of post-translational modifications, protein-protein interactions, and subcellular mobilization of TFs are discussed with regard to the relevance of these regulatory mechanisms for the specific activation of MYBs and bHLHs in response to a given environmental stimulus.展开更多
基金This research was supported by the Structural Genomics Consortium,a registered charity(No.1097737)that receives funds fromthe Canadian Institutes for Health Research,the Canadian Foundation for Innovation,Genome Canada through the Ontario GenomicsInstitute,Glaxo Smith Kline,Karolinska Institutet,the Knut and Alice Wallenberg Foundation,the Ontario lnnovation Trust,the Ontario Ministry for Research and Innovation,Merck&Co.,Inc.,the Novartis Research Foundation,the Swedish Agency for Innovation Systems,the Swedish Foundation for Strategic Research and the Wellcome Trust.
文摘The WD40 domain exhibits aβ-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.
文摘目的运用网络药理学分析方法进行仙灵骨葆治疗骨质疏松症(osteoporosis,OP)的药理机制分析。方法借助中药系统药理学数据库和分析平台以及中药综合数据库获取仙灵骨葆活性成分以及相关靶标,运用Cytoscape 3.7.1软件绘制“活性成分-靶标”网络图,以“osteoporosis”为关键词从GeneCards:The Human Gene Database获取OP相关基因,运用STRING数据分析平台进行PPI(protein-protein interaction)网络分析,运用DAVID数据分析平台进行基因本体(gene ontology,GO)生物过程富集以及京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析,并运用Cytoscape 3.7.1软件绘制“通路-靶标”网络图。结果共获取仙灵骨葆相关活性成分115种,核心活性成分有槲皮素、山奈酚、木犀草素、淫羊藿苷元、丹参酮IIA等。活性成分所涉及的靶标共有301个,核心靶标有PTGS2、PTGS1、ESR1等。PPI网络显示了111种核心蛋白之间的互作关系,主要与调节细胞周期有关。GO富集生物过程经筛选后共获得46项,所得生物过程亦与细胞周期有关,正调控NF-kappaB转录活性因子的过程是OP发生的机制之一,与现有研究符合。KEGG通路富集共获得37项,提示仙灵骨葆治疗OP作用集中于PI3K-Akt、TNF、MAPK、Estrogen等信号通路。结论仙灵骨葆核心活性成分中,黄酮类化合物主要通过调节OPG/RANK/RANKL,抑制破骨细胞,促进成骨细胞分化;淫羊藿苷元可增强成骨细胞活性。核心靶标PTGS2可限制M-CSF以及RANKL的表达,进而影响成骨/破骨细胞分化;雌激素受体与绝经后骨质疏松密切相关。核心通路如PI3K-Akt信号通路可增加骨量、促进成骨细胞分化;TNF信号通路、MAPK信号通路等均与成骨细胞分化有关;雌激素信号通路以及GnRh信号通路为仙灵骨葆干预绝经后骨质疏松提供依据。因此仙灵骨葆干预OP机制是通过多种途径、多种靶标、多种信号通路同时�
文摘Ethylene insensitive 2 （EIN2）, an integral membrane protein of the ER network, has been identified as the central regulator of the ethylene signaling pathway. Still, the mechanism by which the ethylene signal is transferred from the receptors to EIN2 has not been solved yet. Here, we show that protein phosphorylation is a key mechanism to control the interaction of EIN2 and the receptors. In vivo and in vitro fluorescence studies reveal that the kinase domain of the receptors is essential for the interaction. Cyanide, an ethylene agonist, which is known to reduce auto-phosphorylation of the ethylene receptor ethylene resistant 1 （ETR1） or a mutation in the kinase domain of ETR1 that prevents autophosphorylation （H353A）, increases the affinity of the receptors for EIN2. On the other hand, mimicking permanent auto-phosphorylation of ETR1 as in the mutant H353E releases the EiN2-ETR1 interaction from the control by the plant hormone. Based on our data, we propose a novel model on the integration of EIN2 in the ethylene signaling cascade.
文摘In complex, constantly changing environments, plants have developed astonishing survival strategies. These elaborated strategies rely on rapid and precise gene regulation mediated by transcription factors （TFs）. TFs represent a large fraction of plant genomes and among them, MYBs and basic helix-loop-helix （bHLHs） have unique inherent properties specific to plants. Proteins of these two TF families can act as homo- or heterodimers, associate with proteins from other protein families, or form MYB/bHLH complexes to regulate distinct cellular processes. The ability of MYBs and bHLHs to interact with multiple protein part- ners has evolved to keep up with the increased metabolic complexity of multi-cellular organisms. Associ- ation and disassociation of dynamic TF complexes in response to developmental and environmental cues are controlled through a plethora of regulatory mechanisms specifically modulating TF activity. Regulation of TFs at the protein level is critical for efficient and precise control of their activity, and thus provides the mechanistic basis for a rapid on-and-off switch of TF activity. In this review, examples of post-translational modifications, protein-protein interactions, and subcellular mobilization of TFs are discussed with regard to the relevance of these regulatory mechanisms for the specific activation of MYBs and bHLHs in response to a given environmental stimulus.
