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    Dissociation of activated protein C functions by elimination of protein S cofactor enhancement.

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    Authors
    Harmon, Shona
    Preston, Roger J S
    Ainle, Fionnuala Ni
    Johnson, Jennifer A
    Cunningham, Moya S
    Smith, Owen P
    White, Barry
    O'Donnell, James S
    Affiliation
    Haemostasis Research Group, Institute of Molecular Medicine, St James's Hospital, Trinity College, Dublin 8, Ireland.
    Issue Date
    2008-11-07
    MeSH
    Amino Acid Substitution
    Antigens, CD
    Binding Sites
    Cell Line
    Coenzymes
    Endothelial Cells
    Factor VIIIa
    Factor Va
    Humans
    Mutagenesis, Site-Directed
    Peptide Mapping
    Protein C
    Protein S
    Receptor, PAR-1
    Receptors, Cell Surface
    Signal Transduction
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    Citation
    Dissociation of activated protein C functions by elimination of protein S cofactor enhancement. 2008, 283 (45):30531-9 J. Biol. Chem.
    Journal
    The Journal of biological chemistry
    URI
    http://hdl.handle.net/10147/82463
    DOI
    10.1074/jbc.M802338200
    PubMed ID
    18779332
    Abstract
    Activated protein C (APC) plays a critical anticoagulant role in vivo by inactivating procoagulant factor Va and factor VIIIa and thus down-regulating thrombin generation. In addition, APC bound to the endothelial cell protein C receptor can initiate protease-activated receptor-1 (PAR-1)-mediated cytoprotective signaling. Protein S constitutes a critical cofactor for the anticoagulant function of APC but is not known to be involved in regulating APC-mediated protective PAR-1 signaling. In this study we utilized a site-directed mutagenesis strategy to characterize a putative protein S binding region within the APC Gla domain. Three single amino acid substitutions within the APC Gla domain (D35T, D36A, and A39V) were found to mildly impair protein S-dependent anticoagulant activity (<2-fold) but retained entirely normal cytoprotective activity. However, a single amino acid substitution (L38D) ablated the ability of protein S to function as a cofactor for this APC variant. Consequently, in assays of protein S-dependent factor Va proteolysis using purified proteins or in the plasma milieu, APC-L38D variant exhibited minimal residual anticoagulant activity compared with wild type APC. Despite the location of Leu-38 in the Gla domain, APC-L38D interacted normally with endothelial cell protein C receptor and retained its ability to trigger PAR-1 mediated cytoprotective signaling in a manner indistinguishable from that of wild type APC. Consequently, elimination of protein S cofactor enhancement of APC anticoagulant function represents a novel and effective strategy by which to separate the anticoagulant and cytoprotective functions of APC for potential therapeutic gain.
    Language
    en
    ISSN
    0021-9258
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.M802338200
    Scopus Count
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