• Login
    View Item 
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    Structural and functional analysis of the β-chemokine RANTES: Proposal of a three-site binding hypothesis

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Find Full text
    Author
    Burns, Jennifer M.
    Advisor
    Lewis, George K., Ph.D.
    DeVico, Anthony L.
    Date
    1999
    Type
    dissertation
    
    Metadata
    Show full item record
    Other Titles
    Structural and functional analysis of the Beta-chemokine RANTES: Proposal of a three-site binding hypothesis
    Abstract
    Chemokines comprise a family of low molecular weight proteins involved in a variety of biological activities including the activation and regulation of immune responses. A subset of chemokines, including Regulated Upon Activation Normal T Cell Expressed and Secreted (RANTES), Macrophage Inflammatory Protein (MIP)-1alpha, MIP-1beta and Macrophage Derived Chemokine (MDC), block HIV-1 entry of susceptible cells. The anti-viral activity of chemokines is dependent upon binding to 7-transmembrane (TM) G protein-coupled receptors, which also serve as receptors for HIV-1 viral binding to cells. In addition to this dependence upon protein receptors we have demonstrated a reliance of chemokine function on cell surface glycosaminoglycans (GAGs). Through the use of an anti-RANTES monoclonal antibody developed in our laboratory, mAb 4A12, residues in the C-terminal region of RANTES have been identified as those residues critical for GAG binding. Preincubation of mAb 4A12 with RANTES blocks RANTES induced Ca2+ mobilization, inhibits RANTES binding to the cell surface and reverses the HIV-1 anti-viral activity of this chemokine, thus implicating the dependence of chemokine function on cell surface GAGs. Additionally, enzymatic removal of cell surface GAGs from PBMC inhibits the ability of RANTES to mobilize Ca2+ in these cells. Further implication of the importance of GAGs in chemokine function is provided by studies in which cells inherently expressing low levels of cell surface GAGs exhibit reduced ability to mobilize Ca2+ in response to RANTES. Finally, adding back GAGs as soluble complexes to chemokines does not restore chemokine function. Soluble RANTES/GAG complexes are unable to induce Ca2+ mobilization or chemotaxis in susceptible cells; yet they retain HIV-1 anti-viral properties. In conclusion, our data suggest that the current model describing chemokine interactions with protein receptors needs to be extended to include the GAG interaction necessary for functional chemokine binding. Additionally, our findings suggest soluble chemokine/GAG complexes represent 7-TM receptor ligands that no longer elicit the potentially deleterious effects of cell signaling through Ca2+ mobilization and chemotaxis, yet retain their anti-viral activity and therefore represent a potential therapeutic formulation to treat HIV-1 infection.
    Description
    University of Maryland, Baltimore. Microbiology and Immunology. Ph.D. 1999
    Keyword
    Biology, Molecular
    RANTES
    Chemokines, CC
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/1308
    Collections
    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.