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  1. Article ; Online: Repurposing an endogenous degradation domain for antibody-mediated disposal of cell-surface proteins.

    Schmitt, Janika / Poole, Emma / Groves, Ian / Owen, David J / Graham, Stephen C / Sinclair, John / Kelly, Bernard T

    EMBO reports

    2024  Volume 25, Issue 3, Page(s) 951–970

    Abstract: The exquisite specificity of antibodies can be harnessed to effect targeted degradation of membrane proteins. Here, we demonstrate targeted protein removal utilising a protein degradation domain derived from the endogenous human protein Proprotein ... ...

    Abstract The exquisite specificity of antibodies can be harnessed to effect targeted degradation of membrane proteins. Here, we demonstrate targeted protein removal utilising a protein degradation domain derived from the endogenous human protein Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). Recombinant antibodies genetically fused to this domain drive the degradation of membrane proteins that undergo constitutive internalisation and recycling, including the transferrin receptor and the human cytomegalovirus latency-associated protein US28. We term this approach PACTAC (PCSK9-Antibody Clearance-Targeting Chimeras).
    MeSH term(s) Humans ; Proprotein Convertase 9/metabolism ; Serine Endopeptidases ; Proprotein Convertases/metabolism ; Membrane Proteins ; Receptors, LDL/metabolism
    Chemical Substances PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-) ; Proprotein Convertases (EC 3.4.21.-) ; Membrane Proteins ; Receptors, LDL
    Language English
    Publishing date 2024-01-29
    Publishing country England
    Document type Journal Article
    ZDB-ID 2020896-0
    ISSN 1469-3178 ; 1469-221X
    ISSN (online) 1469-3178
    ISSN 1469-221X
    DOI 10.1038/s44319-024-00063-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Non-native fold of the putative VPS39 zinc finger domain.

    Butt, Benjamin G / Scourfield, Edward J / Graham, Stephen C

    Wellcome open research

    2020  Volume 5, Page(s) 154

    Abstract: Background: ...

    Abstract Background:
    Language English
    Publishing date 2020-08-12
    Publishing country England
    Document type Journal Article
    ISSN 2398-502X
    ISSN 2398-502X
    DOI 10.12688/wellcomeopenres.16078.2
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  3. Article ; Online: A Tetrameric Assembly of Saposin A: Increasing Structural Diversity in Lipid Transfer Proteins.

    Shamin, Maria / Spratley, Samantha J / Graham, Stephen C / Deane, Janet E

    Contact (Thousand Oaks (Ventura County, Calif.))

    2021  Volume 4, Page(s) 251525642110523

    Abstract: Saposins are lipid transfer proteins required for the degradation of sphingolipids in the lysosome. These small proteins bind lipids by transitioning from a closed, monomeric state to an open conformation exposing a hydrophobic surface that binds and ... ...

    Abstract Saposins are lipid transfer proteins required for the degradation of sphingolipids in the lysosome. These small proteins bind lipids by transitioning from a closed, monomeric state to an open conformation exposing a hydrophobic surface that binds and shields hydrophobic lipid tails from the aqueous environment. Saposins form a range of multimeric assemblies to encompass these bound lipids and present them to hydrolases in the lysosome. This lipid-binding property of human saposin A has been exploited to form lipoprotein nanodiscs suitable for structural studies of membrane proteins. Here we present the crystal structure of a unique tetrameric assembly of murine saposin A produced serendipitously, following modifications of published protocols for making lipoprotein nanodiscs. The structure of this new saposin oligomer highlights the diversity of tertiary arrangement that can be adopted by these important lipid transfer proteins.
    Language English
    Publishing date 2021-11-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2964312-0
    ISSN 2515-2564 ; 2515-2564
    ISSN (online) 2515-2564
    ISSN 2515-2564
    DOI 10.1177/25152564211052382
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Oropouche Virus Glycoprotein Topology and Cellular Requirements for Glycoprotein Secretion.

    Barbosa, Natalia S / Concha, Juan O / daSilva, Luis L P / Crump, Colin M / Graham, Stephen C

    Journal of virology

    2022  Volume 97, Issue 1, Page(s) e0133122

    Abstract: Oropouche virus (OROV; genus Orthobunyavirus) is the etiological agent of Oropouche fever, a debilitating febrile illness common in South America. We used recombinant expression of the OROV M polyprotein, which encodes the surface glycoproteins Gn and Gc ...

    Abstract Oropouche virus (OROV; genus Orthobunyavirus) is the etiological agent of Oropouche fever, a debilitating febrile illness common in South America. We used recombinant expression of the OROV M polyprotein, which encodes the surface glycoproteins Gn and Gc plus the nonstructural protein NSm, to probe the cellular determinants for OROV assembly and budding. Gn and Gc self-assemble and are secreted independently of NSm. Mature OROV Gn has two predicted transmembrane domains that are crucial for glycoprotein translocation to the Golgi complex and glycoprotein secretion, and unlike related orthobunyaviruses, both transmembrane domains are retained during Gn maturation. Disruption of Golgi function using the drugs brefeldin A and monensin inhibits glycoprotein secretion. Infection studies have previously shown that the cellular endosomal sorting complexes required for transport (ESCRT) machinery is recruited to Golgi membranes during OROV assembly and that ESCRT activity is required for virus secretion. A dominant-negative form of the ESCRT-associated ATPase VPS4 significantly reduces recombinant OROV glycoprotein secretion and blocks virus release from infected cells, and VPS4 partly colocalizes with OROV glycoproteins and membranes costained with Golgi markers. Furthermore, immunoprecipitation and fluorescence microscopy experiments demonstrate that OROV glycoproteins interact with the ESCRT-III component CHMP6, with overexpression of a dominant-negative form of CHMP6 significantly reducing OROV glycoprotein secretion. Taken together, our data highlight differences in M polyprotein processing across orthobunyaviruses, indicate that Golgi and ESCRT function are required for glycoprotein secretion, and identify CHMP6 as an ESCRT-III component that interacts with OROV glycoproteins.
    MeSH term(s) Humans ; Bunyaviridae Infections ; Endosomal Sorting Complexes Required for Transport ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; Orthobunyavirus/genetics ; Viral Proteins/genetics ; Viral Proteins/metabolism
    Chemical Substances Endosomal Sorting Complexes Required for Transport ; Membrane Glycoproteins ; Viral Proteins ; CHMP6 protein, human
    Language English
    Publishing date 2022-12-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/jvi.01331-22
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 609: Show issues Location:
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  5. Article ; Online: Application of error-prone PCR to functionally probe the morbillivirus Haemagglutinin protein.

    Gallo, Giulia / Conceicao, Carina / Tsirigoti, Christina / Willett, Brian / Graham, Stephen C / Bailey, Dalan

    The Journal of general virology

    2021  Volume 102, Issue 4

    Abstract: The enveloped morbilliviruses utilise conserved proteinaceous receptors to enter host cells: SLAMF1 or Nectin-4. Receptor binding is initiated by the viral attachment protein Haemagglutinin (H), with the viral Fusion protein (F) driving membrane fusion. ... ...

    Abstract The enveloped morbilliviruses utilise conserved proteinaceous receptors to enter host cells: SLAMF1 or Nectin-4. Receptor binding is initiated by the viral attachment protein Haemagglutinin (H), with the viral Fusion protein (F) driving membrane fusion. Crystal structures of the prototypic morbillivirus measles virus H with either SLAMF1 or Nectin-4 are available and have served as the basis for improved understanding of this interaction. However, whether these interactions remain conserved throughout the morbillivirus genus requires further characterisation. Using a random mutagenesis approach, based on error-prone PCR, we targeted the putative receptor binding site for SLAMF1 interaction on peste des petits ruminants virus (PPRV) H, identifying mutations that inhibited virus-induced cell-cell fusion. These data, combined with structural modelling of the PPRV H and ovine SLAMF1 interaction, indicate this region is functionally conserved across all morbilliviruses. Error-prone PCR provides a powerful tool for functionally characterising functional domains within viral proteins.
    MeSH term(s) Animals ; Cell Adhesion Molecules/metabolism ; Hemagglutinins, Viral/metabolism ; Host Microbial Interactions ; Membrane Fusion ; Peste-des-petits-ruminants virus/metabolism ; Polymerase Chain Reaction/methods ; Sheep ; Signaling Lymphocytic Activation Molecule Family Member 1/metabolism ; Viral Fusion Proteins/metabolism
    Chemical Substances Cell Adhesion Molecules ; Hemagglutinins, Viral ; Viral Fusion Proteins ; Signaling Lymphocytic Activation Molecule Family Member 1 (169535-43-7)
    Language English
    Publishing date 2021-03-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 219316-4
    ISSN 1465-2099 ; 0022-1317
    ISSN (online) 1465-2099
    ISSN 0022-1317
    DOI 10.1099/jgv.0.001580
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    Zs.A 610: Show issues Location:
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  6. Article ; Online: Molecular mechanism of Afadin substrate recruitment to the receptor phosphatase PTPRK via its pseudophosphatase domain.

    Hay, Iain M / Mulholland, Katie E / Lai, Tiffany / Graham, Stephen C / Sharpe, Hayley J / Deane, Janet E

    eLife

    2022  Volume 11

    Abstract: Protein tyrosine phosphatase receptor-type kappa (PTPRK) is a transmembrane receptor that links extracellular homophilic interactions to intracellular catalytic activity. Previously we showed that PTPRK promotes cell-cell adhesion by selectively ... ...

    Abstract Protein tyrosine phosphatase receptor-type kappa (PTPRK) is a transmembrane receptor that links extracellular homophilic interactions to intracellular catalytic activity. Previously we showed that PTPRK promotes cell-cell adhesion by selectively dephosphorylating several cell junction regulators including the protein Afadin (Fearnley et al, 2019). Here, we demonstrate that Afadin is recruited for dephosphorylation by directly binding to the PTPRK D2 pseudophosphatase domain. We mapped this interaction to a putative coiled coil (CC) domain in Afadin that is separated by more than 100 amino acids from the substrate pTyr residue. We identify the residues that define PTP specificity, explaining how Afadin is selectively dephosphorylated by PTPRK yet not by the closely related receptor tyrosine phosphatase PTPRM. Our work demonstrates that PTP substrate specificity can be determined by protein-protein interactions distal to the active site. This explains how PTPRK and other PTPs achieve substrate specificity despite a lack of specific sequence context at the substrate pTyr. Furthermore, by demonstrating that these interactions are phosphorylation-independent and mediated via binding to a non-catalytic domain, we highlight how receptor PTPs could function as intracellular scaffolds in addition to catalyzing protein dephosphorylation.
    MeSH term(s) Microfilament Proteins/metabolism ; Phosphorylation ; Protein Tyrosine Phosphatases/metabolism ; Substrate Specificity
    Chemical Substances afadin ; Microfilament Proteins ; Protein Tyrosine Phosphatases (EC 3.1.3.48)
    Language English
    Publishing date 2022-10-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.79855
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  7. Article ; Online: Near-native state imaging by cryo-soft-X-ray tomography reveals remodelling of multiple cellular organelles during HSV-1 infection.

    Nahas, Kamal L / Connor, Viv / Scherer, Katharina M / Kaminski, Clemens F / Harkiolaki, Maria / Crump, Colin M / Graham, Stephen C

    PLoS pathogens

    2022  Volume 18, Issue 7, Page(s) e1010629

    Abstract: Herpes simplex virus-1 (HSV-1) is a large, enveloped DNA virus and its assembly in the cell is a complex multi-step process during which viral particles interact with numerous cellular compartments such as the nucleus and organelles of the secretory ... ...

    Abstract Herpes simplex virus-1 (HSV-1) is a large, enveloped DNA virus and its assembly in the cell is a complex multi-step process during which viral particles interact with numerous cellular compartments such as the nucleus and organelles of the secretory pathway. Transmission electron microscopy and fluorescence microscopy are commonly used to study HSV-1 infection. However, 2D imaging limits our understanding of the 3D geometric changes to cellular compartments that accompany infection and sample processing can introduce morphological artefacts that complicate interpretation. In this study, we used soft X-ray tomography to observe differences in whole-cell architecture between HSV-1 infected and uninfected cells. To protect the near-native structure of cellular compartments we used a non-disruptive sample preparation technique involving rapid cryopreservation, and a fluorescent reporter virus was used to facilitate correlation of structural changes with the stage of infection in individual cells. We observed viral capsids and assembly intermediates interacting with nuclear and cytoplasmic membranes. Additionally, we observed differences in the morphology of specific organelles between uninfected and infected cells. The local concentration of cytoplasmic vesicles at the juxtanuclear compartment increased and their mean width decreased as infection proceeded, and lipid droplets transiently increased in size. Furthermore, mitochondria in infected cells were elongated and highly branched, suggesting that HSV-1 infection alters the dynamics of mitochondrial fission/fusion. Our results demonstrate that high-resolution 3D images of cellular compartments can be captured in a near-native state using soft X-ray tomography and have revealed that infection causes striking changes to the morphology of intracellular organelles.
    MeSH term(s) Animals ; Cell Nucleus ; Chlorocebus aethiops ; Herpes Simplex/diagnostic imaging ; Herpesvirus 1, Human/chemistry ; Tomography, X-Ray ; Vero Cells
    Language English
    Publishing date 2022-07-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1010629
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  8. Article ; Online: The crystal structure of vaccinia virus protein E2 and perspectives on the prediction of novel viral protein folds.

    Gao, William N D / Gao, Chen / Deane, Janet E / Carpentier, David C J / Smith, Geoffrey L / Graham, Stephen C

    The Journal of general virology

    2022  Volume 103, Issue 1

    Abstract: The morphogenesis of vaccinia virus (VACV, ... ...

    Abstract The morphogenesis of vaccinia virus (VACV, family
    MeSH term(s) Binding Sites ; Crystallography, X-Ray ; Poxviridae/metabolism ; Protein Binding ; Protein Conformation ; Vaccinia virus/chemistry ; Vaccinia virus/genetics ; Vaccinia virus/physiology ; Viral Proteins/chemistry ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Virus Replication
    Chemical Substances Viral Proteins
    Language English
    Publishing date 2022-02-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 219316-4
    ISSN 1465-2099 ; 0022-1317
    ISSN (online) 1465-2099
    ISSN 0022-1317
    DOI 10.1099/jgv.0.001716
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  9. Article: The lipid transfer protein Saposin B does not directly bind CD1d for lipid antigen loading.

    Shamin, Maria / Benedyk, Tomasz H / Graham, Stephen C / Deane, Janet E

    Wellcome open research

    2019  Volume 4, Page(s) 117

    Abstract: Background: ...

    Abstract Background:
    Language English
    Publishing date 2019-10-18
    Publishing country England
    Document type Journal Article
    ISSN 2398-502X
    ISSN 2398-502X
    DOI 10.12688/wellcomeopenres.15368.2
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  10. Article ; Online: Molecular models should not be published without the corresponding atomic coordinates.

    Graham, Stephen C / Nagar, Bhushan / Privé, Gilbert G / Deane, Janet E

    Proceedings of the National Academy of Sciences of the United States of America

    2019  Volume 116, Issue 23, Page(s) 11099–11100

    MeSH term(s) Deep Learning ; Gaucher Disease ; Glucosylceramidase ; Humans ; Molecular Dynamics Simulation ; Protein Conformation
    Chemical Substances Glucosylceramidase (EC 3.2.1.45)
    Language English
    Publishing date 2019-06-04
    Publishing country United States
    Document type Letter ; Comment
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1904409116
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    Zs.A 1148: Show issues Location:
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