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  • Protein Binding  (6)
  • Nature Publishing Group (NPG)  (6)
  • EDP Sciences
  • National Academy of Sciences
  • 1
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    Crystal structure of the polymerase PA(C)-PB1(N) complex from an avian influenza H5N1 virus (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-07-11
    Description: The recent emergence of highly pathogenic avian influenza A virus strains with subtype H5N1 pose a global threat to human health. Elucidation of the underlying mechanisms of viral replication is critical for development of anti-influenza virus drugs. The influenza RNA-dependent RNA polymerase (RdRp) heterotrimer has crucial roles in viral RNA replication and transcription. It contains three proteins: PA, PB1 and PB2. PB1 harbours polymerase and endonuclease activities and PB2 is responsible for cap binding; PA is implicated in RNA replication and proteolytic activity, although its function is less clearly defined. Here we report the 2.9 angstrom structure of avian H5N1 influenza A virus PA (PA(C), residues 257-716) in complex with the PA-binding region of PB1 (PB1(N), residues 1-25). PA(C) has a fold resembling a dragon's head with PB1(N) clamped into its open 'jaws'. PB1(N) is a known inhibitor that blocks assembly of the polymerase heterotrimer and abolishes viral replication. Our structure provides details for the binding of PB1(N) to PA(C) at the atomic level, demonstrating a potential target for novel anti-influenza therapeutics. We also discuss a potential nucleotide binding site and the roles of some known residues involved in polymerase activity. Furthermore, to explore the role of PA in viral replication and transcription, we propose a model for the influenza RdRp heterotrimer by comparing PA(C) with the lambda3 reovirus polymerase structure, and docking the PA(C) structure into an available low resolution electron microscopy map.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Xiaojing -- Zhou, Jie -- Bartlam, Mark -- Zhang, Rongguang -- Ma, Jianyuan -- Lou, Zhiyong -- Li, Xuemei -- Li, Jingjing -- Joachimiak, Andrzej -- Zeng, Zonghao -- Ge, Ruowen -- Rao, Zihe -- Liu, Yingfang -- England -- Nature. 2008 Aug 28;454(7208):1123-6. doi: 10.1038/nature07120. Epub 2008 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18615018" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Birds/*virology ; Crystallography, X-Ray ; Influenza A Virus, H5N1 Subtype/*enzymology ; Models, Molecular ; Multienzyme Complexes/chemistry/metabolism ; Nucleotides/metabolism ; Peptide Fragments/chemistry/metabolism ; Protein Binding ; Protein Structure, Quaternary ; RNA Replicase/*chemistry/metabolism ; Viral Proteins/*chemistry/*metabolism ; Virus Replication
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Structural insight into the type-II mitochondrial NADH dehydrogenases (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-23
    Description: The single-component type-II NADH dehydrogenases (NDH-2s) serve as alternatives to the multisubunit respiratory complex I (type-I NADH dehydrogenase (NDH-1), also called NADH:ubiquinone oxidoreductase; EC 1.6.5.3) in catalysing electron transfer from NADH to ubiquinone in the mitochondrial respiratory chain. The yeast NDH-2 (Ndi1) oxidizes NADH on the matrix side and reduces ubiquinone to maintain mitochondrial NADH/NAD(+) homeostasis. Ndi1 is a potential therapeutic agent for human diseases caused by complex I defects, particularly Parkinson's disease, because its expression restores the mitochondrial activity in animals with complex I deficiency. NDH-2s in pathogenic microorganisms are viable targets for new antibiotics. Here we solve the crystal structures of Ndi1 in its substrate-free, NADH-, ubiquinone- and NADH-ubiquinone-bound states, to help understand the catalytic mechanism of NDH-2s. We find that Ndi1 homodimerization through its carboxy-terminal domain is critical for its catalytic activity and membrane targeting. The structures reveal two ubiquinone-binding sites (UQ(I) and UQ(II)) in Ndi1. NADH and UQ(I) can bind to Ndi1 simultaneously to form a substrate-protein complex. We propose that UQ(I) interacts with FAD to act as an intermediate for electron transfer, and that NADH transfers electrons through this FAD-UQ(I) complex to UQ(II). Together our data reveal the regulatory and catalytic mechanisms of Ndi1 and may facilitate the development or targeting of NDH-2s for potential therapeutic applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Feng, Yue -- Li, Wenfei -- Li, Jian -- Wang, Jiawei -- Ge, Jingpeng -- Xu, Duo -- Liu, Yanjing -- Wu, Kaiqi -- Zeng, Qingyin -- Wu, Jia-Wei -- Tian, Changlin -- Zhou, Bing -- Yang, Maojun -- England -- Nature. 2012 Nov 15;491(7424):478-82. doi: 10.1038/nature11541. Epub 2012 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23086143" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Electron Transport Complex I/*chemistry/isolation & purification/metabolism ; Mitochondria/*enzymology ; *Models, Molecular ; NAD/chemistry ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/chemistry/enzymology ; Saccharomyces cerevisiae Proteins/*chemistry/isolation & purification/metabolism ; Ubiquinone/chemistry
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Structural basis for the modular recognition of single-stranded RNA by PPR proteins (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-10-29
    Description: Pentatricopeptide repeat (PPR) proteins represent a large family of sequence-specific RNA-binding proteins that are involved in multiple aspects of RNA metabolism. PPR proteins, which are found in exceptionally large numbers in the mitochondria and chloroplasts of terrestrial plants, recognize single-stranded RNA (ssRNA) in a modular fashion. The maize chloroplast protein PPR10 binds to two similar RNA sequences from the ATPI-ATPH and PSAJ-RPL33 intergenic regions, referred to as ATPH and PSAJ, respectively. By protecting the target RNA elements from 5' or 3' exonucleases, PPR10 defines the corresponding 5' and 3' messenger RNA termini. Despite rigorous functional characterizations, the structural basis of sequence-specific ssRNA recognition by PPR proteins remains to be elucidated. Here we report the crystal structures of PPR10 in RNA-free and RNA-bound states at resolutions of 2.85 and 2.45 A, respectively. In the absence of RNA binding, the nineteen repeats of PPR10 are assembled into a right-handed superhelical spiral. PPR10 forms an antiparallel, intertwined homodimer and exhibits considerable conformational changes upon binding to its target ssRNA, an 18-nucleotide PSAJ element. Six nucleotides of PSAJ are specifically recognized by six corresponding PPR10 repeats following the predicted code. The molecular basis for the specific and modular recognition of RNA bases A, G and U is revealed. The structural elucidation of RNA recognition by PPR proteins provides an important framework for potential biotechnological applications of PPR proteins in RNA-related research areas.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yin, Ping -- Li, Quanxiu -- Yan, Chuangye -- Liu, Ying -- Liu, Junjie -- Yu, Feng -- Wang, Zheng -- Long, Jiafu -- He, Jianhua -- Wang, Hong-Wei -- Wang, Jiawei -- Zhu, Jian-Kang -- Shi, Yigong -- Yan, Nieng -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Dec 5;504(7478):168-71. doi: 10.1038/nature12651. Epub 2013 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China [2] Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24162847" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; *Models, Molecular ; Plant Proteins/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; RNA/chemistry/*metabolism ; Zea mays/*chemistry/genetics/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    DNA-repair scaffolds dampen checkpoint signalling by counteracting the adaptor Rad9 (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-11-20
    Description: In response to genotoxic stress, a transient arrest in cell-cycle progression enforced by the DNA-damage checkpoint (DDC) signalling pathway positively contributes to genome maintenance. Because hyperactivated DDC signalling can lead to a persistent and detrimental cell-cycle arrest, cells must tightly regulate the activity of the kinases involved in this pathway. Despite their importance, the mechanisms for monitoring and modulating DDC signalling are not fully understood. Here we show that the DNA-repair scaffolding proteins Slx4 and Rtt107 prevent the aberrant hyperactivation of DDC signalling by lesions that are generated during DNA replication in Saccharomyces cerevisiae. On replication stress, cells lacking Slx4 or Rtt107 show hyperactivation of the downstream DDC kinase Rad53, whereas activation of the upstream DDC kinase Mec1 remains normal. An Slx4-Rtt107 complex counteracts the checkpoint adaptor Rad9 by physically interacting with Dpb11 and phosphorylated histone H2A, two positive regulators of Rad9-dependent Rad53 activation. A decrease in DDC signalling results from hypomorphic mutations in RAD53 and H2A and rescues the hypersensitivity to replication stress of cells lacking Slx4 or Rtt107. We propose that the Slx4-Rtt107 complex modulates Rad53 activation by a competition-based mechanism that balances the engagement of Rad9 at replication-induced lesions. Our findings show that DDC signalling is monitored and modulated through the direct action of DNA-repair factors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536934/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536934/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ohouo, Patrice Y -- Bastos de Oliveira, Francisco M -- Liu, Yi -- Ma, Chu Jian -- Smolka, Marcus B -- F31 GM093588/GM/NIGMS NIH HHS/ -- F31-GM093588/GM/NIGMS NIH HHS/ -- R01 GM097272/GM/NIGMS NIH HHS/ -- R01-GM097272/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jan 3;493(7430):120-4. doi: 10.1038/nature11658. Epub 2012 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14853, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23160493" target="_blank"〉PubMed〈/a〉
    Keywords: Binding, Competitive ; Cell Cycle Checkpoints/*physiology ; Cell Cycle Proteins/antagonists & inhibitors/deficiency/genetics/*metabolism ; Checkpoint Kinase 2 ; DNA Damage/drug effects ; DNA Repair/drug effects/*physiology ; DNA Replication/drug effects ; Endodeoxyribonucleases/deficiency/metabolism ; Enzyme Activation ; Histones/chemistry/genetics/metabolism ; Hydroxyurea/pharmacology ; Intracellular Signaling Peptides and Proteins/metabolism ; Mutation ; Nuclear Proteins/deficiency/metabolism ; Phosphorylation ; Protein Binding ; Protein-Serine-Threonine Kinases/genetics/metabolism ; Saccharomyces cerevisiae/*cytology/drug effects/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Signal Transduction ; Stress, Physiological/drug effects
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-02-10
    Description: First identified as histone-modifying proteins, lysine acetyltransferases (KATs) and deacetylases (KDACs) antagonize each other through modification of the side chains of lysine residues in histone proteins. Acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms, but the corresponding enzymes and substrate-specific functions of the modifications are unclear. Moreover, mechanisms underlying functional specificity of individual KDACs remain enigmatic, and the substrate spectra of each KDAC lack comprehensive definition. Here we dissect the functional specificity of 12 critical human KDACs using a genome-wide synthetic lethality screen in cultured human cells. The genetic interaction profiles revealed enzyme-substrate relationships between individual KDACs and many important substrates governing a wide array of biological processes including metabolism, development and cell cycle progression. We further confirmed that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 and p300. Deacetylation of AMPK enhances physical interaction with the upstream kinase LKB1, leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. These findings provide new insights into previously underappreciated metabolic regulatory roles of HDAC1 in coordinating nutrient availability and cellular responses upstream of AMPK, and demonstrate the importance of high-throughput genetic interaction profiling to elucidate functional specificity and critical substrates of individual human KDACs potentially valuable for therapeutic applications.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277212/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Yu-yi -- Kiihl, Samara -- Suhail, Yasir -- Liu, Shang-Yun -- Chou, Yi-hsuan -- Kuang, Zheng -- Lu, Jin-ying -- Khor, Chin Ni -- Lin, Chi-Long -- Bader, Joel S -- Irizarry, Rafael -- Boeke, Jef D -- U54 RR 020839/RR/NCRR NIH HHS/ -- U54 RR020839/RR/NCRR NIH HHS/ -- U54 RR020839-09/RR/NCRR NIH HHS/ -- England -- Nature. 2012 Feb 8;482(7384):251-5. doi: 10.1038/nature10804.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan. yuyilin@ntu.edu.tw〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22318606" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/chemistry/genetics/*metabolism ; Acetylation ; Biocatalysis ; Catalytic Domain ; Cell Cycle ; Cell Line ; Cell Line, Tumor ; Histone Deacetylase 1/genetics/*metabolism ; Humans ; Lysine/*metabolism ; Phosphorylation ; Protein Binding ; Protein-Serine-Threonine Kinases/metabolism ; RNA Interference ; Substrate Specificity ; p300-CBP Transcription Factors/genetics/*metabolism
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Notum deacylates Wnt proteins to suppress signalling activity (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-03-04
    Description: Signalling by Wnt proteins is finely balanced to ensure normal development and tissue homeostasis while avoiding diseases such as cancer. This is achieved in part by Notum, a highly conserved secreted feedback antagonist. Notum has been thought to act as a phospholipase, shedding glypicans and associated Wnt proteins from the cell surface. However, this view fails to explain specificity, as glypicans bind many extracellular ligands. Here we provide genetic evidence in Drosophila that Notum requires glypicans to suppress Wnt signalling, but does not cleave their glycophosphatidylinositol anchor. Structural analyses reveal glycosaminoglycan binding sites on Notum, which probably help Notum to co-localize with Wnt proteins. They also identify, at the active site of human and Drosophila Notum, a large hydrophobic pocket that accommodates palmitoleate. Kinetic and mass spectrometric analyses of human proteins show that Notum is a carboxylesterase that removes an essential palmitoleate moiety from Wnt proteins and thus constitutes the first known extracellular protein deacylase.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376489/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376489/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kakugawa, Satoshi -- Langton, Paul F -- Zebisch, Matthias -- Howell, Steven A -- Chang, Tao-Hsin -- Liu, Yan -- Feizi, Ten -- Bineva, Ganka -- O'Reilly, Nicola -- Snijders, Ambrosius P -- Jones, E Yvonne -- Vincent, Jean-Paul -- 090532/Wellcome Trust/United Kingdom -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 294523/European Research Council/International -- A10976/Cancer Research UK/United Kingdom -- C375/A10976/Cancer Research UK/United Kingdom -- G0900084/Medical Research Council/United Kingdom -- MC_U117584268/Medical Research Council/United Kingdom -- U117584268/Medical Research Council/United Kingdom -- WT093378MA/Wellcome Trust/United Kingdom -- WT099197MA/Wellcome Trust/United Kingdom -- England -- Nature. 2015 Mar 12;519(7542):187-92. doi: 10.1038/nature14259. Epub 2015 Feb 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC's National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK. ; Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. ; Glycosciences Laboratory, Imperial College London, Department of Medicine, Du Cane Road, London W12 0NN, UK. ; Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. ; Cancer Research UK, Clare Hall Laboratories, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3LD, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25731175" target="_blank"〉PubMed〈/a〉
    Keywords: Acylation ; Animals ; Binding Sites ; Carboxylesterase/chemistry/*metabolism ; Drosophila Proteins/chemistry/*metabolism ; Esterases/chemistry/genetics/*metabolism ; Fatty Acids, Monounsaturated/metabolism ; Glycosylphosphatidylinositols/metabolism ; Glypicans/metabolism ; Humans ; Kinetics ; Ligands ; Mass Spectrometry ; Models, Molecular ; Protein Binding ; Wnt Proteins/*chemistry/*metabolism ; *Wnt Signaling Pathway
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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