BIROn - Birkbeck Institutional Research Online

    Architecturally diverse proteins converge on an analogous mechanism to inactivate Uracil-DNA glycosylase

    Cole, Ambrose R. and Ofer, Sapir and Ryzhenkova, Ksenia and Baltulionis, Gediminas and Hornyak, Peter and Savva, Renos (2013) Architecturally diverse proteins converge on an analogous mechanism to inactivate Uracil-DNA glycosylase. Nucleic Acids Research 41 (18), pp. 8760-8775. ISSN 0305-1048.

    7866.pdf - Published Version of Record
    Available under License Creative Commons Attribution.

    Download (11MB) | Preview


    Uracil-DNA glycosylase (UDG) compromises the replication strategies of diverse viruses from unrelated lineages. Virally encoded proteins therefore exist to limit, inhibit or target UDG activity for proteolysis. Viral proteins targeting UDG, such as the bacteriophage proteins ugi, and p56, and the HIV-1 protein Vpr, share no sequence similarity, and are not structurally homologous. Such diversity has hindered identification of known or expected UDG-inhibitory activities in other genomes. The structural basis for UDG inhibition by ugi is well characterized; yet, paradoxically, the structure of the unbound p56 protein is enigmatically unrevealing of its mechanism. To resolve this conundrum, we determined the structure of a p56 dimer bound to UDG. A helix from one of the subunits of p56 occupies the UDG DNA-binding cleft, whereas the dimer interface forms a hydrophobic box to trap a mechanistically important UDG residue. Surprisingly, these p56 inhibitory elements are unexpectedly analogous to features used by ugi despite profound architectural disparity. Contacts from B-DNA to UDG are mimicked by residues of the p56 helix, echoing the role of ugi’s inhibitory beta strand. Using mutagenesis, we propose that DNA mimicry by p56 is a targeting and specificity mechanism supporting tight inhibition via hydrophobic sequestration.


    Item Type: Article
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Innovation Management Research, Birkbeck Centre for, Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 01 Aug 2013 11:02
    Last Modified: 02 Aug 2023 17:06


    Activity Overview
    6 month trend
    6 month trend

    Additional statistics are available via IRStats2.

    Archive Staff Only (login required)

    Edit/View Item Edit/View Item