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    Identification of amino acid residues critical for aggregation of human CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES. Characterization of active disaggregated chemokine variants.

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    Authors
    Czaplewski, Lloyd G
    McKeating, Jane
    Craven, C Jeremy
    Higgins, Lee D
    Appay, Victor
    Brown, Anthony
    Dudgeon, Tim
    Howard, Lesley A
    Meyers, Tim
    Owen, Jo
    Palan, Shilpa R
    Tan, Paul
    Wilson, Giles
    Woods, Nigel R
    Heyworth, Clare M
    Lord, Brian I
    Brotherton, Deb
    Christison, Richard
    Craig, Stewart
    Cribbes, Scott
    Edwards, R Mark
    Evans, Steve J
    Gilbert, Richard
    Morgan, Pete
    Randle, Eliot
    Schofield, Neil
    Varley, Paul G
    Fisher, Julie
    Waltho, Jonathan P
    Hunter, Michael G
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    Affiliation
    British Biotech Pharmaceuticals Ltd., Watlington Road, Oxford OX4 5LY, United Kingdom. czaplewski@britbio.co.uk
    Issue Date
    1999-06-04
    
    Metadata
    Show full item record
    Abstract
    Human CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation normal T cell expressed) self-associate to form high-molecular mass aggregates. To explore the biological significance of chemokine aggregation, nonaggregating variants were sought. The phenotypes of 105 hMIP-1alpha variants generated by systematic mutagenesis and expression in yeast were determined. hMIP-1alpha residues Asp26 and Glu66 were critical to the self-association process. Substitution at either residue resulted in the formation of essentially homogenous tetramers at 0.5 mg/ml. Substitution of identical or analogous residues in homologous positions in both hMIP-1beta and RANTES demonstrated that they were also critical to aggregation. Our analysis suggests that a single charged residue at either position 26 or 66 is insufficient to support extensive aggregation and that two charged residues must be present. Solution of the three-dimensional NMR structure of hMIP-1alpha has enabled comparison of these residues in hMIP-1beta and RANTES. Aggregated and disaggregated forms of hMIP-1alpha, hMIP-1beta, and RANTES generally have equivalent G-protein-coupled receptor-mediated biological potencies. We have therefore generated novel reagents to evaluate the role of hMIP-1alpha, hMIP-1beta, and RANTES aggregation in vitro and in vivo. The disaggregated chemokines retained their human immunodeficiency virus (HIV) inhibitory activities. Surprisingly, high concentrations of RANTES, but not disaggregated RANTES variants, enhanced infection of cells by both M- and T-tropic HIV isolates/strains. This observation has important implications for potential therapeutic uses of chemokines implying that disaggregated forms may be necessary for safe clinical investigation.
    Citation
    Identification of amino acid residues critical for aggregation of human CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES. Characterization of active disaggregated chemokine variants. 1999, 274 (23):16077-84 J. Biol. Chem.
    Journal
    Journal of Biological Chemistry
    URI
    http://hdl.handle.net/10541/90784
    DOI
    10.1074/jbc.274.23.16077
    PubMed ID
    10347159
    Type
    Article
    Language
    en
    ISSN
    0021-9258
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.274.23.16077
    Scopus Count
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