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  1. Article ; Online: Evolution of the SARS-CoV-2 spike protein in the human host

    Antoni G. Wrobel / Donald J. Benton / Chloë Roustan / Annabel Borg / Saira Hussain / Stephen R. Martin / Peter B. Rosenthal / John J. Skehel / Steven J. Gamblin

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 7

    Abstract: The SARS-CoV-2 spike has been evolving in the human population. The variants of concern alpha and beta evolved to optimise spike openness and so ability to bind its receptor ACE2, the affinity towards the receptor, and stability upon receptor binding. ...

    Abstract The SARS-CoV-2 spike has been evolving in the human population. The variants of concern alpha and beta evolved to optimise spike openness and so ability to bind its receptor ACE2, the affinity towards the receptor, and stability upon receptor binding.
    Keywords Science ; Q
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Structure and binding properties of Pangolin-CoV spike glycoprotein inform the evolution of SARS-CoV-2

    Antoni G. Wrobel / Donald J. Benton / Pengqi Xu / Lesley J. Calder / Annabel Borg / Chloë Roustan / Stephen R. Martin / Peter B. Rosenthal / John J. Skehel / Steven J. Gamblin

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 6

    Abstract: It has been suggested that pangolin coronaviruses may be the origin of SARS-CoV-2. Here the authors show that the Pangolin-CoV spike is structurally closely related to the closed form of SARS-CoV-2 spike and exhibits similar binding properties to human ... ...

    Abstract It has been suggested that pangolin coronaviruses may be the origin of SARS-CoV-2. Here the authors show that the Pangolin-CoV spike is structurally closely related to the closed form of SARS-CoV-2 spike and exhibits similar binding properties to human and pangolin ACE2; although neither spike binds bat ACE2.
    Keywords Science ; Q
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: RET Functions as a Dual-Specificity Kinase that Requires Allosteric Inputs from Juxtamembrane Elements

    Iván Plaza-Menacho / Karin Barnouin / Rachael Barry / Annabel Borg / Mariam Orme / Rakhee Chauhan / Stephane Mouilleron / Rubén J. Martínez-Torres / Pascal Meier / Neil Q. McDonald

    Cell Reports, Vol 17, Iss 12, Pp 3319-

    2016  Volume 3332

    Abstract: Receptor tyrosine kinases exhibit a variety of activation mechanisms despite highly homologous catalytic domains. Such diversity arises through coupling of extracellular ligand-binding portions with highly variable intracellular sequences flanking the ... ...

    Abstract Receptor tyrosine kinases exhibit a variety of activation mechanisms despite highly homologous catalytic domains. Such diversity arises through coupling of extracellular ligand-binding portions with highly variable intracellular sequences flanking the tyrosine kinase domain and specific patterns of autophosphorylation sites. Here, we show that the juxtamembrane (JM) segment enhances RET catalytic domain activity through Y687. This phospho-site is also required by the JM region to rescue an otherwise catalytically deficient RET activation-loop mutant lacking tyrosines. Structure-function analyses identified interactions between the JM hinge, αC helix, and an unconventional activation-loop serine phosphorylation site that engages the HRD motif and promotes phospho-tyrosine conformational accessibility and regulatory spine assembly. We demonstrate that this phospho-S909 arises from an intrinsic RET dual-specificity kinase activity and show that an equivalent serine is required for RET signaling in Drosophila. Our findings reveal dual-specificity and allosteric components for the mechanism of RET activation and signaling with direct implications for drug discovery.
    Keywords receptor tyrosine kinase ; RTK ; structure-function ; phosphorylation ; dual-specificity ; signaling ; oncogene ; Drosophila ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2016-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article: Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN

    Stingele, Julian / Annabel Borg / Ferdinand Alte / Graeme Hewitt / Grzegorz Sarek / J. Mark Skehel / John A. Tainer / Michael Groll / Roberto Bellelli / Sarah L. Maslen / Simon J. Boulton / Susan E. Tsutakawa / Svend Kjær

    Molecular cell. 2016 Nov. 17, v. 64, no. 4

    2016  

    Abstract: Covalent DNA-protein crosslinks (DPCs) are toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription. Little was known about DPC-specific repair mechanisms until the recent identification of a DPC- ... ...

    Abstract Covalent DNA-protein crosslinks (DPCs) are toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription. Little was known about DPC-specific repair mechanisms until the recent identification of a DPC-processing protease in yeast. The existence of a DPC protease in higher eukaryotes is inferred from data in Xenopus laevis egg extracts, but its identity remains elusive. Here we identify the metalloprotease SPRTN as the DPC protease acting in metazoans. Loss of SPRTN results in failure to repair DPCs and hypersensitivity to DPC-inducing agents. SPRTN accomplishes DPC processing through a unique DNA-induced protease activity, which is controlled by several sophisticated regulatory mechanisms. Cellular, biochemical, and structural studies define a DNA switch triggering its protease activity, a ubiquitin switch controlling SPRTN chromatin accessibility, and regulatory autocatalytic cleavage. Our data also provide a molecular explanation on how SPRTN deficiency causes the premature aging and cancer predisposition disorder Ruijs-Aalfs syndrome.
    Keywords chromatin ; crosslinking ; DNA ; eggs ; enzyme activity ; eukaryotic cells ; hypersensitivity ; metalloproteinases ; neoplasms ; toxicity ; ubiquitin ; Xenopus laevis ; yeasts
    Language English
    Dates of publication 2016-1117
    Size p. 688-703.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2016.09.031
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Identification of an LGP2-associated MDA5 agonist in picornavirus-infected cells

    Safia Deddouche / Delphine Goubau / Jan Rehwinkel / Probir Chakravarty / Sharmin Begum / Pierre V Maillard / Annabel Borg / Nik Matthews / Qian Feng / Frank J M van Kuppeveld / Caetano Reis e Sousa

    eLife, Vol

    2014  Volume 3

    Abstract: The RIG-I-like receptors RIG-I, LGP2, and MDA5 initiate an antiviral response that includes production of type I interferons (IFNs). The nature of the RNAs that trigger MDA5 activation in infected cells remains unclear. Here, we purify and characterise ... ...

    Abstract The RIG-I-like receptors RIG-I, LGP2, and MDA5 initiate an antiviral response that includes production of type I interferons (IFNs). The nature of the RNAs that trigger MDA5 activation in infected cells remains unclear. Here, we purify and characterise LGP2/RNA complexes from cells infected with encephalomyocarditis virus (EMCV), a picornavirus detected by MDA5 and LGP2 but not RIG-I. We show that those complexes contain RNA that is highly enriched for MDA5-stimulatory activity and for a specific sequence corresponding to the L region of the EMCV antisense RNA. Synthesis of this sequence by in vitro transcription is sufficient to generate an MDA5 stimulatory RNA. Conversely, genomic deletion of the L region in EMCV generates viruses that are less potent at stimulating MDA5-dependent IFN production. Thus, the L region antisense RNA of EMCV is a key determinant of innate immunity to the virus and represents an RNA that activates MDA5 in virally-infected cells.
    Keywords RIG-I-like receptor ; MDA5 ; LGP2 ; picornavirus ; EMCV ; antiviral immunity ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2014-02-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article: Oncogenic RET Kinase Domain Mutations Perturb the Autophosphorylation Trajectory by Enhancing Substrate Presentation In trans

    Plaza-Menacho, Iván / Annabel Borg / Judith Murray-Rust / Karin Barnouin / Kerry Goodman / Neil Q. McDonald / Phillip Knowles / Rubén J. Martínez-Torres / Stephane Mouilleron

    Molecular cell. 2014 Mar. 06, v. 53

    2014  

    Abstract: To decipher the molecular basis for RET kinase activation and oncogenic deregulation, we defined the temporal sequence of RET autophosphorylation by label-free quantitative mass spectrometry. Early autophosphorylation sites map to regions flanking the ... ...

    Abstract To decipher the molecular basis for RET kinase activation and oncogenic deregulation, we defined the temporal sequence of RET autophosphorylation by label-free quantitative mass spectrometry. Early autophosphorylation sites map to regions flanking the kinase domain core, while sites within the activation loop only form at later time points. Comparison with oncogenic RET kinase revealed that late autophosphorylation sites become phosphorylated much earlier than wild-type RET, which is due to a combination of an enhanced enzymatic activity, increased ATP affinity, and surprisingly, by providing a better intermolecular substrate. Structural analysis of oncogenic M918T and wild-type RET kinase domains reveal a cis-inhibitory mechanism involving tethering contacts between the glycine-rich loop, activation loop, and αC-helix. Tether mutations only affected substrate presentation but perturbed the autophosphorylation trajectory similar to oncogenic mutations. This study reveals an unappreciated role for oncogenic RET kinase mutations in promoting intermolecular autophosphorylation by enhancing substrate presentation.
    Keywords adenosine triphosphate ; enzyme activity ; glycine (amino acid) ; mass spectrometry ; mutation ; protein phosphorylation
    Language English
    Dates of publication 2014-0306
    Size p. 738-751.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2014.01.015
    Database NAL-Catalogue (AGRICOLA)

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